Bio 151 lec 3 2012 2013 (part 2)

ADAPTIVE IMMUNITY

Monday, July 9, 2012

IMPORTANT POINTS

• What is Adaptive Immune Response?

• What is the difference between T and B cell function for adaptive immune response?

• What are Antigen-Presenting Cells (APCs)?

• What is the role of MHC in adaptive response?


ADAPTIVE IMMUNE RESPONSE

• initiated when antigen receptors of lymphocytes recognize the antigens

• B lymphocytes receptors (membrane-bound-antibodies): proteins, polysaccharides, lipids, nucleic acids, small chemicals in soluble or cell surface-associated form

• humoral

• generated against many types of microbial cell walls and soluble antigens

• T lymphocytes receptors: peptide fragments of protein antigens

• presented by specialized display molecules on host cells

• cell-mediated

• generated only against the protein antigens of microbes that are associated with host cells


BARRIERS TO THE INDUCTION OF ADAPTIVE

IMMUNE RESPONSE

• low frequency of naive lymphocytes in the body specific for any one antigen (may be less than 1 in every 100,000) which has to LOCATE and REACT rapidly to the antigen wherever it is introduced

• different kinds of microbes need to be combated by different types of adaptive response (even to the same microbe at different stages of its life)

• e.g. virus (blood stages = antibodies; host cell stages = CTLs)


ANTIGEN CAPTURE &

PRESENTATION


ANTIGEN RECOGNITION BY T LYMPHOCYTES

• The majority of T lymphocytes recognize peptide antigens that are bound to and displayed by the major histocompatibility complex (MHC) molecules of antigen-presenting cells (APCs).

• MHC: genetic locus whose principal products function as the peptide display molecules of the immune system

• MHC restriction: unique for each individual; different clones of T cells can see peptides only when these peptides are displayed by that individual's MHC molecules


ANTIGEN RECOGNITION BY T LYMPHOCYTES

• DUAL SPECIFICITY OF T-CELLS:

• T cell receptor (TCR) recognizes some residues of peptide antigen

• T cell receptor (TCR) recognizes residues of the MHC molecule that is displaying that peptide


ANTIGEN-PRESENTING CELLS (APCs)

• specialized cells that capture microbial antigens and display them for recognition by T lymphocytes

• “professional” APCs: ability to both display antigens for T cells and provide the additional signals needed to activate naive T cells

• Differentiated effector T cells again need to see antigens presented by various APCs, to activate the effector functions of the T cells in humoral and cell-mediated immune responses.

• How does APCs present antigens to trigger immune responses?

• What is the role of MHC molecules in these processes?


CAPTURE OF PROTEIN ANTIGENS BY APCs

• Protein antigens of microbes that enter the body are captured by professional APCs and are concentrated in the peripheral lymphoid organs where immune are initiated



• Epithelia contain a population of professional APCs that belong to the lineage of dendritic cells

• The same cells are present in the T-cell rich areas of peripheral lymphoid organs, and in smaller number, in most other organs



• Langerhans cells: epidermal dendritic cells in the skin

• “immature” = inefficient in stimulating T-lymphocytes

• capture the antigens:

• phagocytosis = for particulate antigens

• pinocytosis = soluble antigens




• During their migration, and probably in response to the microbe the dendritic cells mature; and in the lymph nodes, the dendritic cells present antigens to naive T-lymphocytes

• Dendritic cells at different stages of their maturation may express different membrane proteins

• Immature dendritic cells express surface receptors that capture microbial antigens, whereas mature dendritic cells express high levels of MHC molecules and co-stimulators, which function to stimulate T- cells



• Different types of APCs serve distinct functions in T-cell dependent immune response

• Dendritic cells: principal inducers of such responses because dendritic cells are the most potent APCs for activating naive T-lymphocytes; Dendritic cells not only initiate T-cell responses but may also influence the nature of the response

• Macrophages: phagocytose microbes and display the antigens of these microbes to effector T-cells, which activate the macrophage to kill the microbes

• B-lymphocytes: ingest protein antigens and display them to helper T cells; this process is important for the development of humoral immune responses

• NOTE: all nucleated cells can present antigens derived from microbes in the cytoplasm to CTLs



• Professional APCs may also be involved in initiating the responses of CD8+ T-lymphocytes to the antigens of intracellular microbes

• CROSS-PRESENTATION (or cross-priming):

• one cell-type, the professional APCs, can present the antigens of other cells, the infected cells, and prime (or activate) naive T lymphocytes specific for these antigens

• The professional APCs that ingest infected cells may also present the microbial antigens toCD4+ helper T-lymphocytes. Thus, both classes of T lymphocytes, CD4+ and CD8+ cells, specific for the same microbe are activated close to one another

• IMPORTANCE: for the antigen-stimulated differentiation of naive CD8+ T cells to effector CTLs which often requires help from CD4+ T-cells. Once the CD8+ T cells have differentiated into CTLs, they kill infected host cells without any need for professional APCs or signals other than recognition of antigen


CROSS-PRIMING


How are these antigens displayed to

T- lymphocytes?!


ANSWER: MHC MOLECULES


MAJOR HISTOCOMPATIBILITY

COMPLEX (MHC)

• membrane proteins on APCs that display peptide antigens for recognition by T lymphocytes

• discovered as the genetic locus that is the principal determinant of acceptance or rejection of tissue grafts exchanged between individuals

• individuals that are identical at their MHC locus (inbred animals and identical twins) will accept grafts from one another, and individuals that differ at their MHC loci will reject such grafts

• physiologic function: to display peptides derived from protein antigens to antigen-specific T-lymphocyte



COMPLEX (MHC)

• MHC locus is a collection of genes found in all mammals

• Human MHC proteins are called human leukocyte antigens (HLA), because these proteins were discovered as antigens of leukocytes that could be identified with specific antibodies; the genes encoding these molecules make up the HLA locus

• In all species, the MHC locus contains two sets of highly polymorphic genes, called the class 1 and class II MHC genes

• These genes encode the class I and class II MHC molecules that display peptides to T-cells



COMPLEX (MHC)


CLASS I & CLASS II MHC MOLECULES ARE MEMBRANE PROTEINS THAT EACH

CONTAINS A PEPTIDE-BINDING CLEFT AT ITS AMINO TERMINAL END


CLASS I & CLASS II MHC MOLECULES ARE MEMBRANE PROTEINS THAT EACH

CONTAINS A PEPTIDE-BINDING CLEFT AT ITS AMINO TERMINAL END


PROPERTIES OF MHC GENES & MOLECULES



• Class I molecules are expressed on all nucleated cells, but Class II molecules are expressed mainly on professional APCS such as dendritic cells, and on macrophages and B lymphocytes



• The peptide-binding clefts of MHC molecules bind peptides derived from protein antigens and display these peptides for recognition by T cells


FEATURES OF PEPTIDE BINDING TO MHC MOLECULES






PROCESSING OF PROTEIN

ANTIGENS


PATHWAYS OF INTRACELLULAR PROCESSING OF PROTEIN



CLASS II MHC

PATHWAY


CLASS I MHC

PATHWAY


MHC & CD4+/CD8+ T CELLS


QUESTIONS???


ANTIGEN RECOGNITION


IMPORTANT POINTS

• How do the antigen receptors of lymphocytes recognize extremely diverse antigens and transmit quite conserved activating signals to the cells?

• How is the vast diversity of receptor structures generated in lymphocytes?

• NOTE: The diversity of antigen recognition implies the existence of many structurally different antigen receptor proteins, more than can be reasonably encoded in the inherited genome (germline) = THUS, there must be special mechanisms for generating this diversity!


ANTIGEN RECEPTORS OF LYMPHOCYTES


ANTIGEN RECEPTORS OF LYMPHOCYTES

ANTIBODY TCR


RECALL...ANTIBODIES


RECALL...ANTIBODIES


RECALL...ANTIBODIES


STRUCTURE OF T-CELL RECEPTOR FOR ANTIGENS


RECOGNITION OF A PEPTIDE-MHC COMPLEX BY A TCR


ANTIGEN RECOGNITION


ANTIGEN RECOGNITION


LYMPHOCYTE MATURATION


PRODUCTION OF DIVERSE ANTIGEN

RECEPTORS


RECOMBINATION & EXPRESSION OF Ig GENES


MECHANISMS OF DIVERSITY IN ANTIGEN RECEPTORS


MATURATION & SELECTION OF B-LYMPHOCYTES


MATURATION & SELECTION OF MHC-RESTRICTED T-LYMPHOCYTES


QUESTIONS???


NEXT MEETING: HUMORAL &

CELLULAR IMMUNE

RESPONSE


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Bio 151 lec 3 2012 2013 (part 2)

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