Self- and Nonself-Recognition by C-Type Lectins on Dendritic Cells

19 Feb 2004 12:0 AR AR210-IY22-02.tex AR210-IY22-02.sgm LaTeX2e(2002/01/18)P1: IKH10.1146/annurev.immunol.22.012703.104558

Annu. Rev. Immunol. 2004. 22:33–54doi: 10.1146/annurev.immunol.22.012703.104558

Copyright c© 2004 by Annual Reviews. All rights reservedFirst published online as a Review in Advance on September 15, 2003

SELF- AND NONSELF-RECOGNITION BY

C-TYPE LECTINS ON DENDRITIC CELLS

Teunis B.H. Geijtenbeek,1 Sandra J. van Vliet,1

Anneke Engering,1 Bert A. ’t Hart,2,3

and Yvette van Kooyk11Department of Molecular Cell Biology and Immunology, Vrije Universiteit MedicalCenter Amsterdam, 1081 BT Amsterdam, Netherlands; email: Y.vankooyk @vumc.nl2Department of Immunobiology, Biomedical Primate Research Center,2280 GH Rijswijk, Netherlands3Department of Immunology, Erasmus Medical Centre, 3015 GE Rotterdam, Netherlands

Key Words DC-SIGN, carbohydrates, antigen recognition, pathogen, dendriticcells

■ Abstract Dendritic cells (DCs) are highly efficient antigen-presenting cells(APCs) that collect antigen in body tissues and transport them to draining lymphnodes. Antigenic peptides are loaded onto major histocompatibility complex (MHC)molecules for presentation to na¨ıve T cells, resulting in the induction of cellular andhumoral immune responses. DCs take up antigen through phagocytosis, pinocytosis,and endocytosis via different groups of receptor families, such as Fc receptors forantigen-antibody complexes, C-type lectin receptors (CLRs) for glycoproteins, andpattern recognition receptors, such as Toll-like receptors (TLRs), for microbial anti-gens. Uptake of antigen by CLRs leads to presentation of antigens on MHC class Iand II molecules. DCs are well equipped to distinguish between self- and nonself-antigens by the variable expression of cell-surface receptors such as CLRs and TLRs.In the steady state, DCs are not immunologically quiescent but use their antigen-handling capacities to maintain peripheral tolerance. DCs are continuously samplingand presenting self- and harmless environmental proteins to silence immune acti-vation. Uptake of self-components in the intestine and airways are good examplesof sites where continuous presentation of self- and foreign antigens occurs with-out immune activation. In contrast, efficient antigen-specific immune activation oc-curs upon encounter of DCs with nonself-pathogens. Recognition of pathogens byDCs triggers specific receptors such as TLRs that result in DC maturation and sub-sequently immune activation. Here we discuss the concept that cross talk betweenTLRs and CLRs, differentially expressed by subsets of DCs, accounts for the differ-ent pathways to peripheral tolerance, such as deletion and suppression, and immuneactivation.

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34 GEIJTENBEEK ET AL.

DENDRITIC CELLS

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that areseeded throughout peripheral tissues to act as sentinels that process and presentantigen to mount adequate immune responses. Depending on the type of antigen,and the tissue localization, the immune response is suppressed or activated (1,2). DCs differentiate from bone marrow stem cells and migrate as precursor DCsinto the blood. Immature DCs populate all body tissues where they sample ei-ther self- or nonself-antigens. Self-antigens can be derived from their innocuousenvironment, such as necrotic and apoptotic cells that need to be scavenged be-fore they disintegrate. Alternatively, nonself-antigens are foreign products frominvading pathogens that need to be eliminated. The main function of DCs is tocapture antigen for processing and presentation as antigenic fragments on majorhistocompatibility complex (MHC) class I or II molecules to na¨ıve T cells (1). Ina steady-state situation, prior to acute infection and inflammation, DCs are in animmature state and are not fully differentiated to carry out their known roles as in-ducers of immunity. They are not unresponsive as they actively circulate throughtissues and into lymphoid organs, capturing self-antigens as well as innocuousenvironmental proteins. In a state of alarm such as a microbial invasion, or mas-sive cell death, immature DCs receive simultaneous activation signals through thebinding of conserved molecular motifs by pattern recognition receptors, such asToll-like receptors (TLRs) or specific TNF family members (1, 3). This results inDC maturation and migration to secondary lymphoid organs, where DCs presentthe processed antigens to na¨ıve T cells and induce antigen-specific immune re-sponses. The maturation and migration of DCs is carefully orchestrated by certainchemokines, adhesion molecules, and co-stimulatory molecules. These factorscontrol the differentiation stages of the DC and direct the migration of the variousDC subtypes (4). Chemokines generated within the lymph nodes attract na¨ıve Tcells toward the DC, enabling maximal exposure of MHC-peptide complexes tonaı̈ve T cells. Adhesion molecules are crucial for the cellular interactions that DCsundergo during their journey from bone marrow through blood into peripheral or-gans and subsequently lymphoid tissues, where they enable DC–T cell interactionsnecessary for T cell activation.

Recently, many novel cell-surface molecules have been identified that are in-volved in antigen capture by DCs. In particular, a large diversity of C-type lectinreceptors (CLRs) has been identified on DCs that are involved in the recognitionof a wide range of carbohydrate structures on antigens (5, 6). Especially the res-ident immature tissue DCs express a wide variety of C-type lectins that seem tobe involved in the specific recognition of both self-antigens and pathogens. Al-though little is known about their specific carbohydrate recognition profile andantigen specificity, it is becoming evident that some of the CLRs, such as Dectin-1, DC-SIGN, and the mannose receptors (MRs), are more than just scavengerreceptors and they may regulate signaling events or function as cell adhesionreceptors.

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ANTIGEN RECOGNITION BY C-TYPE LECTINS ON DC 35

One of the major enigmas in immunology concerns those regulatory mecha-nisms that maintain the unresponsiveness of self-reactive T cells in the normalrepertoire to self-antigens while at the same time allowing effective immune re-actions to foreign antigens to be mounted. We propose here that both of thesefunctions are coordinated by DCs, using distinct characteristics of the variousreceptor classes, such as CLRs and TLRs, present on their surface.

ANTIGEN RECOGNITION RECEPTORS ON DCs:TLRs AND CLRs

Next to MHC, CD1, and FcR, the main DC receptors engaged in the direct recogni-tion of characteristic molecular patterns on antigens are the TLRs and CLRs (7–9).TLRs are pathogen recognition receptors (10) that recognize characteristic molec-ular patterns present in microbial lipids, lipoprotein, lipopolysaccharides (LPS),nucleic acids, or bacterial DNA, as well as factors secreted upon tissue damagesuch as heat shock proteins (Hsp 70) (11, 12). The recognition by TLRs triggersintracellular signaling cascades that result in DC maturation and the induction ofinflammatory cytokines, ultimately leading to T cell activation (7, 10). In contrast,CLRs recognize specific carbohydrate structures on self-antigens or cell wall com-ponents of pathogens. Their main function is to internalize antigens for degradationin lysosomal compartments to enhance antigen processing and presentation by DCs(5, 13). To date, several CLRs have been found to function as pathogen recogni-tion receptors, whereas only a few have been shown to recognize self-antigens.Specific pathogens target CLRs to circumvent processing and presentation and toprevent immune activation. By targeting certain CLRs, such as DEC-205, tolerancecan be induced in vivo, indicating that the sampling of self-antigens by specificCLRs may set the stage for tolerance induction and immune suppression (2). Thesefindings illustrate a possible function for CLRs in the recognition of a wide vari-ety of carbohydrate structures on self-glycoproteins to allow specific homeostaticcontrol to self-antigens and to mediate cellular processes such as cell signaling,cell adhesion, and migration (5). In contrast, specific pathogens benefit from theircapacity to target host C-type lectins, using the function of the C-type lectins toinduce nonresponsiveness against their processed antigens with the aim to pro-mote their survival by escaping immune activation. There are new indications thatTLRs and CLRs communicate with each other, and it is proposed that the cross talkbetween TLRs and CLRs may fine-tune the balance between immune activationand tolerance (14–17). Recognition of self-antigen by CLRs alone will favor im-mune suppression, whereas pathogen recognition or self-recognition in a situationof danger where both TLRs and CLRs are triggered induces immune activation.Thus, in a steady-state situation, antigens are captured by CLRs to maintain toler-ance, whereas in a dangerous situation, CLR binding to the same antigen occursin the presence of TLR triggering, and the immunostimulatory function of TLRsoverrules the tolerizing function of CLRs, resulting in immune activation (18).

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Depending on their tissue localization and differentiation state, DCs expressunique sets of TLRs and CLRs. Many different CLRs are expressed by immaturemonocyte-derived DCs (5), such as the MR (CD206) (19), DEC-205 (CD205)(20), DC-SIGN (CD209) (21), BCDA-2 (22), Dectin-1 (23), DCIR (24), DCAL-1(25), C-LEC (26), and DC-ASGPR (27)/MGL-1 (28). In contrast, only a few C-type lectins have been identified on blood DCs and Langerhans cells. Langerhanscells express specifically Langerin (CD207) (29) and DEC-205, whereas plasma-cytoid DCs express BDCA-2, Dectin-1, and DEC-205. Many C-type lectins arenot exclusively expressed by DCs but are also expressed by other APCs such asmacrophages. However, other CLRs are DC-specific, such as DEC-205 on murineDCs (30), Langerin on human Langerhans cells (29), and DC-SIGN expression thatis confined to human DCs both in vitro and in vivo (31). DC-SIGN is abundantlyexpressed on both monocyte- and CD34+-derived DCs, as well as dermal DCs, butnot by Langerhans cells in the epidermis (21). In vivo, DC-SIGN is expressed byimmature DCs in peripheral tissues like skin, gut mucosa, cervix, rectum, placenta,and lung, as well as on DCs present in lymphoid tissues, lymph nodes, tonsils, andspleen (21, 32). Two DC-SIGN-positive DC precursor populations that differ inCD14 expression were found to be present in peripheral blood (33). Importantly,the expression of DC-SIGN is strongly dependent on Th2 cytokines such as IL-4,linking high expression of DC-SIGN on DCs to Th2 polarization (34).

CLRs are highly expressed on immature DCs that are efficient in antigen captureand processing, whereas upon maturation CLR expression is readily decreased.Reflecting the large variety of CLRs on DC subsets, a large diversity of TLRsare also expressed by these DC subsets (35). Myeloid DCs express TLR2, 4, and6, whereas plasmacytoid DCs express TLR7 and 9 (36, 37). That distinct DCsubsets carry different sets of TLRs and CLRs raises the possibility that subsetsof DCs recognize distinct classes of self- and nonself-antigens to induce toler-ance or activate immunity. The expression pattern of CLRs and TLRs in vivois as yet an unexplored field, but it needs to be developed as knowledge aboutexpression of certain sets of antigen recognition receptors is essential for ourunderstanding of how these DC subsets handle antigens and induce or suppressimmunity.

FUNCTIONAL CHARACTERISTICS OF C-TYPE LECTINS

Most CLRs on DCs are type II transmembrane proteins, with the exception ofthe MR and DEC-205, which are both type I transmembrane proteins (5). AllC-type lectins contain carbohydrate-binding activity based on the presence of atleast one carbohydrate recognition domain (CRD) (9). The CRD of the C-typelectin DC-SIGN is a globular protein that contains two Ca2+-binding sites, ofwhich one directly coordinates the binding specificity of the carbohydrate struc-tures (38). Calcium binding is essential for the function of CLRs because muta-tion of either Ca2+-binding site in DC-SIGN leads to the loss of ligand binding

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(39). Depending on the amino acid sequence, the CRD bears specificity foreither mannose, galactose, or fucose structures. However, binding of these car-bohydrate structures to the different CLRs is also dependent on carbohydratebranching, spacing, and multivalency. The involvement of specific C-type lectinsin ligand binding is often demonstrated by the ability of specific carbohydratecomponents, such as mannan, or a calcium chelator to block the interaction.However, coexpression of several CLRs—with the same carbohydrate specifi-city and calcium-dependency—on one DC subset makes it essential to use CLR-specific blocking antibodies to demonstrate specific CLR functions.

RECOGNITION OF CARBOHYDRATES BY C-TYPE LECTINS

Several C-type lectins expressed by DCs have specificity for mannose-containingcarbohydrates. However, each C-type lectin may recognize a unique branchingand positioning of mannose residues on a given pathogen or self-antigen structure(19, 21, 27, 40–44). Also, multimerization of the receptor influences carbohydratespecificity (42). For example, the neck domain of DC-SIGN consists of 7 repetitivesequences that are thought to effect oligomer formation. The oligomerization oflectin domains alters the affinity and specificity of carbohydrate recognition (45).Strikingly, MR and MGL-1 form trimers, whereas DC-SIGN has been shown toform tetramers (42), which may partly explain the differences in carbohydratespecificity (38). To date, little is known about the carbohydrate and antigen speci-ficity of CLRs expressed by DCs. The MR, DC-SIGN, and Langerin have beendemonstrated to recognize mannose-containing carbohydrates but with a differentspecificity that is dictated by the branching of the mannose structures. Whereasthe MR recognizes end-standing single mannose structures or di-mannose clusters,DC-SIGN recognizes, besides end-standing di-mannoses, also internal mannose-branched structures (high mannose) (21, 38, 41). The MR has also been shown torecognize fucose-, glucose- and GlcNAc—but not galactose-containing structures(46).

Screening panels of synthetic glycoconjugates, containing mannose, galac-tose, and fucose residues, including their multimeric derivatives, can be used todelineate the specificity of C-type lectins (47–49). These experiments revealedthat DC-SIGN recognizes a profile of carbohydrates distinct from what was ini-tially thought. Next to recognizing mannose-containing structures, DC-SIGN hasa higher specificity for fucose-containing carbohydrates, which is present in Lewisblood group antigens (Lex, Ley, Lea, Leb) that contain fucose residues in differentanomeric linkages (49, 50). In contrast, the MR does not recognize Lex struc-tures even though it has specificities for fucose (41). Sialylation of Lex (yieldingsialyl-Lex), a L-, E-, and P-selectin ligand, completely abrogates recognition byDC-SIGN, indicating that DC-SIGN has a distinct carbohydrate specificity fromthe selectins that mediate leukocyte rolling (49). The CLR ASGPR/MGL-1 israther unique in its carbohydrate-recognition profile, as it primarily recognizes

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galactose but not mannose or fucose residues (27, 51). Some CLRs have overlap-ping carbohydrate specificity and recognize a wide variety of carbohydrate struc-tures, yet others have a rather unique recognition profile. Many of the recognizedcarbohydrate structures, such as Lex and mannose-containing carbohydrates, canbe present on both self-glycoproteins and pathogens, supporting a role for C-typelectins in both self- and pathogen-recognition.

CLRs IN THE REGULATION OF ANTISELFIMMUNE REACTIONS

Many C-type lectins serve as antigen receptors (5). The main function of C-typelectins on DCs is to interact with a large variety of conserved molecular patternspresent on self- and nonself-antigens (52, 53). Most C-type lectins contain putativeinternalization motifs, such as the di-leucine motif and the tri-acidic clusters (54),and their function as endocytic receptors has been demonstrated by their capacityto internalize specific antibodies (5). For some C-type lectins, internalization ofCLR-specific murine IgG antibodies was shown to lead to antigen presentationto murine IgG-specific CD4+ T cells. Most C-type lectins containing a tri-acidiccluster (DEC-205, DC-SIGN, BDCA-2, Dectin-1, and CLEC-1) target internalizedantigens to lysosomes and MHC class II+ late endosomes (Figure 1) (20, 55). Incontrast, other C-type lectins, such as the MR, quickly recycle via early endosomesto ensure uptake of large amounts of antigen (Figure 1) (19). This process ismediated by a tyrosine-based motif in the cytoplasmic tail of the MR (56). Similarto DEC-205, DC-SIGN contains a tri-acidic cluster in its cytoplasmic tail, andaccordingly DC-SIGN-ligand complexes are targeted to lysosomal compartmentswhere ligands are processed for MHC class II presentation to T cells, indicating animportant function for DC-SIGN as an antigen receptor (13). However, DC-SIGNalso contains a di-leucine motif that appears to be essential for rapid internalizationof soluble ligands by DC-SIGN (Figure 1) (13). Although most C-type lectins areendocytic receptors, it is unknown whether they can direct antigens to differentintracellular compartments.

To date, the exact mechanism of antigen presentation by C-type lectins in vivois poorly understood. Antigens targeted to the CLRs DEC-205 and the MR areprocessed by DCs for presentation on both MHC class I and II, leading to a morespecific and efficient antigen presentation (57–59). Other studies show that MRis engaged in the presentation of glycolipids via CD1. Uptake ofM. tuberculosislipoarabinomannan (LAM) by DCs through MR resulted in presentation by CD1bto specific T cells (60).

C-type lectin receptors are not only involved in the recognition of pathogensbut they might also contribute to the capture and presentation of glycosylated self-antigens. For example, the MR recognizes lysosomal hydrolases, certain collagen-like peptides in serum (61), and thyroglobulin, a well known self-antigen (43), andmay have a role in autoimmunity (62).

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The natural ligands of DEC-205 and its carbohydrate specificity are currentlyunknown. However, using DEC-205-specific antibodies as surrogate ligands, it hasbeen demonstrated that this CLR mediates routing to MHC class II compartmentsand facilitates a 30–100 times more efficient presentation of captured antigensas compared to the MR (20). Similarly, targeting of DEC-205 using anti-DEC-205 antibodies facilitates efficient antigen presentation by MHC class I molecules(63). In vivo targeting of ovalbumin conjugated with DEC-205-specific antibodiesto DCs induces tolerance, whereas coinjection of agonistic anti-CD40 antibodyreverses the outcome from tolerance to prolonged T cell activation and immu-nity (Figure 2A) (55, 63). These experiments elegantly demonstrate that understeady-state conditions in vivo, DCs have the capacity to induce peripheral T cellunresponsiveness, but a robust immune response is induced to the same antigen inthe presence of danger signals (Figure 2A). In summary, in vivo antigen targetingto DCs under steady-state conditions seems to induce deletional tolerance whenimmunity is induced in conditions where DC maturation is triggered.

Tolerance can be achieved with small amounts of protein and is manifestedas profound unresponsiveness, indicating that the mechanisms dictating toleranceand immune activation are strictly regulated. More than 50% of the proteins in thehuman body are glycosylated, and it can be envisaged that in the steady state, DCsdefine immunological self on the basis of sugar structures, thereby suppressingthe self-reactivity of the T cell repertoire. When in a danger state, DC matura-tion is induced by a microbial infection: the repertoire and the immune attack areselectively focused on elimination of the pathogen. CLRs in particular play animportant role in the capture and uptake of self-antigens by binding to specific car-bohydrate structures present on cells or secreted proteins that need to be scavenged.Also, the in vivo localization of CLR expression hints to the important functionof CLRs in self-antigen clearance and their potential role in tolerance induction.For example, DC-SIGN is highly expressed by DCs in placenta at the interface ofmother/child antigen transmission, a site of immune tolerance (32, 64). DC-SIGNis also highly expressed on ellipsoids in spleen at those sites where a direct contactbetween blood and tissue exists to enable antigen clearance from blood, withoutinduction of an immune response. DC-SIGN is highly expressed in lymph nodeson DCs located in the T cell area as well as on immature DCs located at the siteclose to the efferent sinus (21, 32). Moreover, the structural related CLR of DC-SIGN, L-SIGN/DC-SIGNR, is highly expressed on liver sinusoidal endothelialcells (LSECs), a resident APC population of monocyte origin (65, 66). LSECsare known to mediate the clearance of many potentially antigenic proteins fromthe circulation in a similar manner as DCs in lymphoid organs/peripheral tissues(67). The tissue localization and ligand-binding properties of L-SIGN support aphysiological role for this CLR in antigen clearance. LSECs can induce tolerancein the liver (68), and L-SIGN may be involved in the antigen capture. In particular,apoptotic cells alter their glycosylation pattern (69) and are therefore candidatesto be cleared by L-SIGN in the liver. Another CLR, Endo-180, which is expressedon endothelium, appears to be involved in the clearance of collagen, which under

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steady-state conditions is continuously synthesized and degraded during the nor-mal turnover of connective tissue (70). This process involves specific binding ofcollagen fibrils to the CLR, followed by the cellular uptake and degradation of theinternalized collagen in the lysosomal compartment (71).

CLR AND THE RECOGNITION OF SELF-GLYCOPROTEINSTO MEDIATE CELL ADHESION

DC-SIGN functions as a cell-adhesion receptor that regulates DC migration (72)and DC-T cell interaction (21) through its interaction with the self-glycoproteinsICAM-2 and ICAM-3, respectively. The natural ligand of DC-SIGN on lympho-cytes, ICAM-3, contains N-linked glycosylations consisting of high-mannose-typeoligosaccharides (73), and enzymatic removal of the N-linked carbohydrates fromICAM-3Fc completely abrogates its binding to DC-SIGN (39). These data indicatethat DC-SIGN recognizes high-mannose-type carbohydrates on ICAM-3, but thespecific carbohydrate structure on ICAM-3 has not yet been identified. Resultssuggest that DC-SIGN does not preferentially bind to all ICAM-3-expressingcells, but only interacts with specific leukocyte subsets. These findings hint tocell-specific glycosylation of ICAM-3 enabling only binding of subsets of cells(K. van Gisbergen, unpublished results).

The other self-glycoprotein, ICAM-2, plays a central role in DC migration andhoming to secondary lymphoid tissues. Although DC-SIGN binds to both ICAM-2 and ICAM-3 under static conditions, only the DC-SIGN-ICAM-2 interactionresists the shear stresses encountered under physiological flow conditions (33).Remarkably, DC-SIGN behaves as a DC-specific rolling receptor for ICAM-2 andis thus functionally similar to the selectins, which are well known for their regu-lation of leukocyte rolling upon carbohydrate-structure recognition (74). Despitethe fact that both DC-SIGN and selectins mediate leukocyte rolling, they have adistinct carbohydrate-recognition repertoire, i.e., Lex versus sialyl-Lex, illustratingthat they may be involved in transendothelial migration at distinct sites.

Recently, it has been reported that the MR also recognizes sialyl-Lex structuresexpressed by endothelial cells; thus this CLR may also contribute to the rollinginteractions of DCs (75). The MR is also expressed by lymphatic endothelial cells,where it can interact with L-selectin to mediate lymphocyte binding (76). Thisillustrates that several CLRs, including DC-SIGN, selectins, and the MR, can reg-ulate leukocyte rolling and migration, processes regulated by the expression of theappropriate carbohydrate structures on target cells. Whereas DC-SIGN recognizeshigh-mannose and Lex structures, both the MR and the selectins mediate rollingupon recognition of endothelial ligands that present sialyl- Lex structures. We pre-dict that tissue-restricted glycosylation of ICAM-2 and expression of sialyl Lex

and Lex structures may direct the migration of DC to particular sites. Cell- andtissue-specific glycosylation of a protein (post-translational modification) is drivenby the tissue-specific expression of certain glycosyltransferases and glycosidases,

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which add or remove specific carbohydrate residues, respectively. The expressionof a large variety of these enzymes is tightly regulated during the differentiationand activation of leukocytes and by specific cytokines. Because specific carbo-hydrate structures dictate the specificity of the interaction with certain CLRs, theimpact of altered glycosylation of a given glycoprotein can change the recognitionby CLRs and subsequently alter cell-cell interactions (77). Indeed, tissue- and cell-specific homing and migration by selectins are regulated by the expression of aselected set of fucosyltransferases resulting in expression of specific carbohydratestructures (78). Understanding the carbohydrate specificity of DC-SIGN and otherDC-expressed CLRs is a recent topic of interest in the field of glycobiology andimmunology (49) (http://web.mit.edu/glycomics/consortium).

CLRs: A TARGET FOR PATHOGENS

Some CLRs have been implicated in the recognition of pathogens, yet specificpathogens target CLRs to escape immune activation. This paradox raises the ques-tion of whether the main function of CLRs is to capture pathogens or to recognizeself-antigen and suppress immunity. Both the MR and DC-SIGN have been demon-strated to capture pathogens, and in particular DC-SIGN is targeted by pathogensthat seek immune escape. The identification of DC-SIGN as a DC-specific ad-hesion receptor (21) revealed its 100% identity to the previously cloned (HIV)-1envelope-binding C-type lectin, and as such the first pathogen that interacts withDC-SIGN was discovered (79, 80). DC-SIGN does not only interact with M- andT-tropic HIV-1, HIV-2, and simian immunodeficiency virus (SIV) (61, 80–82), butalso with other viruses such as Ebola virus, Cytomegalovirus, Hepatitis C virus,and Dengue virus (83–90). DC-SIGN recognizes the viral envelope glycoproteinsthat contain a relatively large number of N-linked carbohydrates. In particular, forHIV-1, Ebola, and Dengue virus it has been demonstrated that differential glyco-sylation of the envelope glycoproteins affects DC-SIGN binding and subsequentlyinfection and viral transmission (91, 92). Other viruses that do express heavilyglycosylated glycoproteins on their surface (e.g., VSV) fail to interact with DC-SIGN (93), suggesting a certain degree of specificity in DC-SIGN recognition.Even though it is likely that high-mannose structures on gp120 are recognized byDC-SIGN (91, 92, 94), it is not ruled out that protein-protein interactions may alsobe involved in binding (39).

Additionally, nonviral pathogens can interact with DC-SIGN.Helicobacter py-lori and certainKlebsiella pneumoniastrains interact with DC-SIGN throughLPS that contain Lex and mannose structures, respectively (49).Mycobacteriumtuberculosisinteracts with DC-SIGN on DCs via the mannose cap of the cell-wall component ManLAM (49, 95). Parasites such asLeishmania amastigotesand Schistosoma mansoniare recognized by DC-SIGN through the mannose-capped surface lipophosphoglycan (49, 96) and the Lex-positive soluble egg anti-gen (50), respectively, whereas the specific structure for fungusCandida albicans

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is not yet identified (97). In conclusion, a large panel of pathogens are pri-marily captured by DCs through binding to the DC-specific C-type lectinDC-SIGN.

DC-SIGN: A RECEPTOR TO ALLOWVIRAL DISSEMINATION

In contrast to CD4, DC-SIGN does not function as a classical HIV-1 entry re-ceptor (80) but acts as an HIV-1 transreceptor that binds HIV-1 and transmits thevirus very efficiently to neighboring permissive target cells (80). The presence ofDC-SIGN+ DCs in mucosal tissues and DC-SIGN+ DC precursors in blood thatefficiently transmit HIV-1 to T cells (98) makes DC-SIGN a candidate to be a keymolecule in HIV-1 dissemination both after sexual transmission and through bloodcontamination (99, 100). DC-SIGN not only captures and transmits HIV-1, but italso enhances T cell infection because at low virus titers, CD4/CCR5-expressingcells are not detectable as being infected by HIV-1 without the assistance of DC-SIGN in trans (80). Conditions in which the number of HIV-1 particles is limitinglikely occur shortly after infection in vivo. This suggests that DC-SIGN may notonly be required for HIV-1 transmission from mucosa to lymphoid tissues, but alsofor efficient infection of T cells.

Neutralization of the pH within the HIV-1-containing compartments or pre-vention of internalization by deletion of the DC-SIGN cytoplasmic region abro-gates DC-SIGN-mediated enhanced transinfection of T cells (93). This indicatesthat the internalization of the infectious HIV-1 particle is essential for transinfec-tion of T cells. The clathrin-dependent sorting pathway likely mediates DC-SIGNendocytosis and recycling through recognition of the di-leucin motif. Clathrin-independent pathways may additionally be used during virus-induced DC-SIGNinternalization.

It is presently unclear whether intact HIV-1 virions escape targeting to lyso-somes, as was described for other internalized DC-SIGN-ligands (13), and howthese virions are protected against full processing. Whereas DC-SIGN-bound lig-ands are internalized for processing in lysosomal compartments, HIV-1 bound toDC-SIGN is remarkably stable and remains infective for prolonged periods (Fig-ure 1) (80). Enzymatic digestion of cell surface–bound HIV-1 demonstrated thatHIV-1 is protected and probably hides within cellular compartments close to thecell membrane without being degraded. An immunofluorescence study by Kwonet al. has demonstrated that HIV-1 is indeed internalized upon binding to DC-SIGNinto nonlysosomal acidic organelles (93). In mature DCs, DC-SIGN is targeted toearly endosomal compartments, in which HIV-1 would be protected against degra-dation (13), suggesting that maturation of DCs by HIV-1 may lead to its alteredinternalization. Finding a way to override this mechanism and to target internal-ized DC-SIGN-HIV complexes to lysosomes would facilitate HIV-1 processing inDCs, and it would enhance specific anti-HIV-1 immune responses while reducinginfection of T cells (Figure 1) (13, 93).

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At high concentrations, HIV-1 can infect DCs in cultures that coexpress CD4and chemokine receptors (57, 101, 102). HIV-1 can replicate in immature as well asin mature DCs that interact with T cells (82, 103). In particular, the initial quantityof virus that enters the mucosal tissues may be decisive in whether DCs becomeinfected by HIV-1 or whether the virus is captured for efficient transinfection of Tcells (80). The Nef protein of HIV-1 appears to be crucial for DC–T cell binding(104). In addition, Nef can interact with the cell-sorting machinery to downregulateexpression levels of CD4 and MHC class I and thus facilitate immune evasion(101). Expression of Nef in immature DCs results in a redistribution of DC-SIGNto the cell surface, thus reducing DC-SIGN internalization in favor of cell-surfaceexpression and facilitating increased cell adhesion and virus transmission to T cells(82). Redistribution of DC-SIGN requires the di-leucine motif in the cytoplasmictail of DC-SIGN, as well as a di-leucine motif in Nef, indicating that Nef interfereswith the recognition of DC-SIGN by the sorting machinery (82).

Recently, other CLRs, such as Langerin and MR, were shown to bind HIVgp120 through recognition of mannose-containing carbohydrates present on HIVgp120 (105–108). However, only the MR has been shown to capture and transmitHIV-1 to permissive T cells similar to DC-SIGN (109). Interestingly, HIV bound tothe MR on macrophages has a lower half-life than free HIV-1, and no transmissionoccurred beyond 24 h after initial capture of the virus (109). The finding thatthe longevity of HIV-1 when captured by DC-SIGN exceeds five days indicatesthat the HIV-1 internalization routes are different for the MR and DC-SIGN. Onmonocyte-derived immature DCs, DC-SIGN is the major HIV-1 receptor despitecoexpression of the MR (80). It will be interesting to find out whether differentsubsets of DCs expressing different arrays of CLRs handle HIV-1 differently,leading either to immune escape and HIV dissemination or to immune activationthrough processing and presentation of the virus.

CLR AND TLR CROSS TALK

Nonviral pathogens also target CLRs to infect DCs (89–90, 96). Most striking isthat several pathogens subvert DC-SIGN function to escape immune surveillanceby a mechanism other than HIV-1 (110).

Mycobacterium tuberculosisis a potent inducer of T helper 1 (Th1)-polarizedimmune response, and mycobacterial components have often been shown to stim-ulate expression of costimulatory molecules and IL-12 production in DCs throughTLR2 and TLR4 triggering. An immunocompetent host controls infection withM. tuberculosis, yet complete eradication of the pathogen does not occur. Whenthe immune response is impaired, active disease can develop, normally throughreactivation of quiescent organisms or in some cases through reinfection. Althoughalveolar macrophages are the primary targets for infection by mycobacteria, DCsare important for activation of the cellular immune response (111, 112).M. tuber-culosisandM. bovisbacillus Calmette-Gu´erin (BCG) strongly bind to DC-SIGN

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through their mannose-capped cell-wall component lipoarabinomannan (Man-LAM) (15, 95). ManLAM is abundant in slow-growing mycobacteria compris-ing virulent species such asM. tuberculosisandM. leprea. AraLAM, which isabundant in fast-growing atypical avirulent mycobacteria such asM. smegmatis,M. fortuitum, andM. chelonae, does not interact with DC-SIGN, indicating thatparticular virulent strains have adapted to target DC-SIGN (15, 113).

DC-SIGN is a major receptor of DC for mycobacteria (15). Although immatureDCs also express high levels of the receptors MR, CD11b, and CD11c, whichcan mediate binding of mycobacteria by macrophages (114, 115), DC-SIGN-specific antibodies, in contrast to MR-specific antibodies, inhibit the interactionof DCs with bothM. bovisBCG and ManLAM by more than 80% (15). Capturedmycobacteria are targeted to the lysosomal compartment (15, 113), although it isnot yet clear whether some mycobacteria can escape degradation in DCs. However,DCs do not support mycobacterial growth due to IL-10-induced reversion of DCmaturation (116, 117).

The cell-wall component ManLAM, which is considered to be a virulence fac-tor, is also secreted in vivo by macrophages infected withM. tuberculosis(118,119). This suggests that mycobacteria may specifically secrete ManLAM to inter-fere with the immune function of bystander DCs. Strikingly, secreted ManLAMfrom mycobacteria-infected macrophages targets CLRs to alter the immune re-sponse through cross talk between CLRs and TLRs (Figure 2B) (13, 15, 120). Inparticular, binding of the mycobacterial component ManLAM to immature DCsinhibited LPS-mediated IL-12 induction (120). This study suggested that Man-LAM binding to the MR on immature DCs interferes with TLR4 signaling. Nigouet al. implicated MR as the main ManLAM-binding C-type lectin on DCs (120).However, recent work shows that ManLAM inhibits LPS-induced DC maturationby interacting with DC-SIGN because LPS-induced DC maturation in the pres-ence of ManLAM is fully restored by inhibiting DC-SIGN-ManLAM interactionwith specific antibodies (15). Also, viableM. bovisBCG induced DC maturation(15), probably through TLR2 and TLR4 signaling (121), and as observed withLPS, ManLAM specifically blocked theM. bovisBCG-induced DC maturation(15). The inhibition of DC maturation caused by ManLAM binding to DC-SIGNcould be fully restored by antibodies against DC-SIGN (15). This illustrates thatDC-SIGN, upon binding ManLAM, delivers a negative signal forM. bovisBCG-induced DC maturation, presumably induced via TLR4 (Figure 2B). Furthermore,ManLAM binding to DC-SIGN induced the production of the anti-inflammatorycytokine IL-10 by LPS-activated DCs (15). The inhibition of DC maturation andthe induction of IL-10 may contribute to the virulence of mycobacteria; imma-ture DCs and IL-10-treated DCs are not only less efficient in the stimulation ofT cell responses but also induce a state of antigen-specific tolerance (Figure 2B)(122). Thus, pathogen recognition by DC-SIGN may modulate DC-induced im-mune responses, shifting the balance from immune activation toward impairmentof immune responses, which would be beneficial to pathogen survival. How DC-SIGN signals are propagated within DCs is not yet clear, but the presence of

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immunoreceptor tyrosine-based activation motifs (ITAMs) in its cytoplasmic tailsuggests that DC-SIGN is capable of direct signaling (54).

Both DC-SIGN and Dectin-1 contain ITAMs. DCIR contains an immunore-ceptor tyrosine-based inhibitory motif (ITIM) (54, 123, 124). The function ofthese so-called activating or inhibitory signaling motifs is not yet clear, but recentdata demonstrate that upon pathogen recognition by CLRs, such as DC-SIGN andDectin-1, intracellular signaling processes initiated by TLR activation are inhib-ited (15–17). The C-type lectin Dectin-1, recognized as a receptor for the yeastcomponent zymosan, acts in concert with TLR2/4 to enhance the production ofIL-12 and TNFα in DCs, facilitating a Th1 response (16, 17). These studies demon-strated that the cytoplasmic tail of Dectin-1, and in particular the ITAM motif, isinvolved in enhancing stimulatory capacity. Remarkably, DC-SIGN also containsan ITAM motif, yet when targeted byM. tuberculosis, the immune response isdriven toward immunosuppression by the induction of IL-10 and the inhibitionof DC maturation. These studies demonstrate that the collaborative recognitionof distinct microbial components by different classes of innate immune receptors(CLRs and TLRs) is crucial for orchestrating inflammatory or inhibitory responses.The balance between TLR stimulation and C-type lectin occupation may fine-tuneregulatory mechanisms to allow appropriate immune responses. The inflamma-tory and pathogenic consequence of this recognition is dependent on both thereceptor repertoire and the functional cooperation between the signals generateddownstream of receptor-ligand interaction. Yet we should not forget that in somepathological situations, the pathogens have evolved to direct the balance towardimmune suppression, for instance by the secretion and production of a large quan-tity of soluble factors that target CLRs such as DC-SIGN (15).

CONCLUDING REMARKS AND FUTURE DIRECTIONS

Within the past few years, various CLRs have been identified on DCs. The pat-tern of CLR expression depends on the DC subset. Whereas CLRs are abundantlyexpressed by immature DCs in peripheral tissues, the expression of most CLRsis rapidly downregulated upon DC maturation. Although CLRs initially were re-garded as scavenger receptors, it is now clear that they bind a variety of anti-gens via specific recognition of particular carbohydrate profiles with interestingand important consequences. CLR-bound antigens are processed and presented toT cells, thus enhancing antigen presentation and immune activation. Strikingly,in vivo targeting of CLRs induces immune suppression, hinting to an importantfunction of CLRs in the tolerance toward self-antigen. It has been well establishedthat T cells reactive to self-antigen are part of the normal immune repertoire ofmice, nonhuman primates, and humans at frequencies comparable to patients withautoimmune diseases. The fact that most of us do not develop autoimmune dis-eases shows that the autoreactive cells are kept under tight control. As the majorityof self-antigens are glycosylated, we postulate that tolerance is maintained by the

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interaction with CLRs on DCs. However, when DCs obtain stimuli that resultin maturation, such as upon pathogen recognition by TLR or CD40 triggering,this signaling overrules the tolerizing effects of CLRs. Certain pathogens that canstimulate DCs via TLRs, likely in the presence of CD40 engagement, can breakthe tolerant state. In an experimental setting, this is modeled when self-antigen isinjected in an emulsion with strong bacterial antigens. Under these conditions themechanisms that keep autoreactive T cells quiescent are broken, and autoimmunediseases develop.

The human body uses regulatory T cells (Tregs) to control unwanted immunereactivity (125). Natural Tregs are localized in the thymus and inhibit T cell ac-tivation primarily via cell-cell contact, whereas inducible Tregs are distributedover the lymphoid organs and exert their suppressive activity via secretion of cy-tokines. It has yet to be proven whether DCs that have taken up autoantigen viatheir CLRs present processed antigen to inducible Tregs and in this way maintainsystemic tolerance. It will be very important to understand if all CLRs processantigen in a similar fashion and whether they all contribute to self-tolerance orwhether some CLRs may also process antigen to induce antigen-specific immuneactivation, especially since some CLRs contain ITIM or ITAM motifs.

Intriguingly, specific pathogens target CLRs to escape immunosurveillance andto promote their survival by sequestration in DCs and by reducing their powerfulantigen-presenting capacities. After HIV-1 was shown to bind DC-SIGN to hidewithin DCs, the same sophisticated escape mechanism was shown to be exploitedby a steadily expanding repertoire of viruses that cause serious diseases in thehuman population, including CMV, Ebola virus, and Dengue virus. Also, nonviralpathogens may target DC-SIGN to escape immune surveillance.M. tuberculosistargets DC-SIGN to inhibit DC maturation and induce IL-10 production by amechanism that interferes with TLR signaling. Our present knowledge of thevariety of CLRs expressed on DCs, the exact mechanisms via which they exerttheir functions, and the positive or negative interaction with other receptor families(TLRs) is still very limited. It will be challenging to understand the function ofC-type lectins in signaling and communication to other receptors on DCs, such asTLRs.

A common feature of pathogens that interact with DC-SIGN is that they causechronic infections that may persist lifelong, and secondly, that a disturbed Th1/Th2balance by the pathogens is central to their persistence. Therefore, pathogens thattarget DC-SIGN may not only infect DCs but also shift the Th1/Th2 balance towarda response in favor of their persistence.

The intriguing question arises of whether oligosaccharides on cellular counter-structures allow DC migration to specific sites as well as DC interactions withspecific T cell subsets. Future research addressing carbohydrate-recognition pro-files by C-type lectins and the regulation of glycosylation on its cellular counter-structures by post-translational modification will provide insight as to how thesecell-surface receptors mediate cellular interactions and regulate DC function. Also,understanding the carbohydrate-recognition element present on self-antigens or

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pathogens that regulate the interaction with a specific CLR may have consequencesfor how the pathogen or antigen is processed by DC.

ACKNOWLEDGMENTS

We thank all former and present members of our group, including our collabo-rators whose work has helped shape the ideas expressed here. We are gratefulto the Netherlands Organisation for Scientific Research (NWO) Pioneer grant016.036.607 and VENI grant 916.36.009, the AIDS Foundation, the Dutch Diges-tive Diseases Foundation (MLDS), and the Dutch Cancer Foundation (NKB) fortheir financial support.

TheAnnual Review of Immunologyis online at http://immunol.annualreviews.org

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ANTIGEN RECOGNITION BY C-TYPE LECTINS ON DC C-1

Figure 1 Internalization of antigens by different C-type lectins leads to antigen rout-ing to distinct intracellular compartments. The MR rapidly internalizes antigens anddetaches from the antigen in early endosomes to cycle back to the cell surface. Theantigen is subsequently targeted to the lysosomes. DC-SIGN internalizes antigens tolysosomes to allow loading on MHC class II molecules. HIV-1 interferes with theDC-SIGN internalization pathway to hide within early endosomes in an infectiousform. Internalization pathways of CLRs are dependent on their cytoplasmic regions.Many CLRs contain different internalization signals.

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C-2 GEIJTENBEEK ET AL.

Figure 2 Balanced activation of C-type lectins (CLRs) and Toll-like receptors (TLRs)determines DC differentiation and the resulting immune responses. (A) Recognition ofself-antigens by CLRs can lead to a differential outcome of immune response. Targetingof CLRs with self-antigens, in the absence of TLR triggering, leads to processing of anti-gen, without any DC maturation leading to tolerance induction. During inflammatoryresponses, TLRs are triggered, and subsequently DCs maturate. When simultaneouslyself-antigens are captured by CLRs, T cell reactivity against self-antigens is initiatedleading to autoimmunity. (B) Cross talk between CLRs and TLRs is essential in fine-tuning immune responses. Recognition of pathogens such as mycobacteria by the CLRDC-SIGN and TLRs can lead to immune activation when the TLR-signal overrules thatof the CLR, and this includes DC differentiation. This can occur when low amounts ofpathogens target the CLR. When high concentrations of pathogens target the CLR DC-SIGN, the immune tolerizing signals can overrule the TLR-induced signals and inhibitDC differentiation, leading to immune suppression and pathogen survival.

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P1: FRK

February 27, 2004 22:25 Annual Reviews AR210-FM

Annual Review of ImmunologyVolume 22, 2004

CONTENTS

FRONTISPIECE—Leonard A. Herzenberg and Leonore A. Herzenberg x

GENETICS, FACS, IMMUNOLOGY, AND REDOX: A TALE OF TWO LIVESINTERTWINED, Leonard A. Herzenberg and Leonore A. Herzenberg 1

SELF- AND NONSELF-RECOGNITION BY C-TYPE LECTINS ONDENDRITIC CELLS, Teunis B.H. Geijtenbeek, Sandra J. van Vliet,Anneke Engering, Bert A. ’t Hart, and Yvette van Kooyk 33

TRANSCRIPTIONAL CONTROL OF EARLY B CELL DEVELOPMENT,Meinrad Busslinger 55

UBIQUITIN LIGASES AND THE IMMUNE RESPONSE, Yun-Cai Liu 81

LIGANDS FOR L-SELECTIN: HOMING, INFLAMMATION, AND BEYOND,Steven D. Rosen 129

INTEGRINS AND T CELL–MEDIATED IMMUNITY, Jonathan T. Pribila,Angie C. Quale, Kristen L. Mueller, and Yoji Shimizu 157

MULTIPLE ROLES OF ANTIMICROBIAL DEFENSINS, CATHELICIDINS,AND EOSINOPHIL-DERIVED NEUROTOXIN IN HOST DEFENSE,De Yang, Arya Biragyn, David M. Hoover, Jacek Lubkowski,and Joost J. Oppenheim 181

STARTING AT THE BEGINNING: NEW PERSPECTIVES ON THE BIOLOGYOF MUCOSAL T CELLS, Hilde Cheroutre 217

THE BCR-ABL STORY: BENCH TO BEDSIDE AND BACK,Stephane Wong and Owen N. Witte 247

CD40/CD154 INTERACTIONS AT THE INTERFACE OF TOLERANCEAND IMMUNITY, Sergio A. Quezada, Lamis Z. Jarvinen, Evan F. Lind,and Randolph J. Noelle 307

THE THREE ES OF CANCER IMMUNOEDITING, Gavin P. Dunn,Lloyd J. Old, and Robert D. Schreiber 329

AUTOIMMUNE AND INFLAMMATORY MECHANISMS INATHEROSCLEROSIS, Georg Wick, Michael Knoflach, and Qingbo Xu 361

THE DYNAMIC LIFE OF NATURAL KILLER CELLS, Wayne M. Yokoyama,Sungjin Kim, and Anthony R. French 405

v

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vi CONTENTS

THE ROLE OF COMPLEMENT IN THE DEVELOPMENT OF SYSTEMICLUPUS ERYTHEMATOSUS, Anthony P. Manderson, Marina Botto,and Mark J. Walport 431

DROSOPHILA: THE GENETICS OF INNATE IMMUNE RECOGNITION ANDRESPONSE, Catherine A. Brennan and Kathryn V. Anderson 457

RAGS AND REGULATION OF AUTOANTIBODIES, Mila Jankovic,Rafael Casellas, Nikos Yannoutsos, Hedda Wardemann,and Michel C. Nussenzweig 485

THE ROLE OF SUPPRESSORS OF CYTOKINE SIGNALING (SOCS)PROTEINS IN REGULATION OF THE IMMUNE RESPONSE,Warren S. Alexander and Douglas J. Hilton 503

NATURALLY ARISING CD4+ REGULATORY T CELLS FORIMMUNOLOGIC SELF-TOLERANCE AND NEGATIVE CONTROLOF IMMUNE RESPONSES, Shimon Sakaguchi 531

PHOSPHOINOSITIDE 3-KINASE: DIVERSE ROLES IN IMMUNE CELLACTIVATION, Jonathan A. Deane and David A. Fruman 563

IMMUNITY TO TUBERCULOSIS, Robert J. North and Yu-Jin Jung 599

MOLECULAR DEFECTS IN HUMAN SEVERE COMBINEDIMMUNODEFICIENCY AND APPROACHES TO IMMUNERECONSTITUTION, Rebecca H. Buckley 625

PHYSIOLOGICAL CONTROL OF IMMUNE RESPONSE ANDINFLAMMATORY TISSUE DAMAGE BY HYPOXIA-INDUCIBLEFACTORS AND ADENOSINE A2A RECEPTORS, Michail V. Sitkovsky,Dmitriy Lukashev, Sergey Apasov, Hidefumi Kojima, Masahiro Koshiba,Charles Caldwell, Akio Ohta, and Manfred Thiel 657

T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS, Jaehyuk Choi,David R. Enis, Kian Peng Koh, Stephen L. Shiao, and Jordan S. Pober 683

IMMUNOLOGICAL MEMORY TO VIRAL INFECTIONS,Raymond M. Welsh, Liisa K. Selin, and Eva Szomolanyi-Tsuda 711

CENTRAL MEMORY AND EFFECTOR MEMORY T CELL SUBSETS:FUNCTION, GENERATION, AND MAINTENANCE,Federica Sallusto, Jens Geginat, and Antonio Lanzavecchia 745

CONTROL OF T CELL VIABILITY, Philippa Marrack and John Kappler 765

ASTHMA: MECHANISMS OF DISEASE PERSISTENCE AND PROGRESSION,Lauren Cohn, Jack A. Elias, and Geoffrey L. Chupp 789

CD1: ANTIGEN PRESENTATION AND T CELL FUNCTION,Manfred Brigl and Michael B. Brenner 817

CHEMOKINES IN INNATE AND ADAPTIVE HOST DEFENSE: BASICCHEMOKINESE GRAMMAR FOR IMMUNE CELLS, Antal Rotand Ulrich H. von Andrian 891

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CONTENTS vii

INTERLEUKIN-10 AND RELATED CYTOKINES AND RECEPTORS,Sidney Pestka, Christopher D. Krause, Devanand Sarkar, Mark R. Walter,Yufang Shi, and Paul B. Fisher 929

INDEXESSubject Index 981Cumulative Index of Contributing Authors, Volumes 12–22 1011Cumulative Index of Chapter Titles, Volumes 12–22 1018

ERRATAAn online log of corrections to Annual Review of Immunology chaptersmay be found at http://immunol.annualreviews.org/errata.shtml

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Self- and Nonself-Recognition by C-Type Lectins on Dendritic Cells

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