Zamai GIC 2010 How NK Cells Influence Desease

8/3/2019 Zamai GIC 2010 How NK Cells Influence Desease

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How NK cells influence disease

Loris ZamaiLoris Zamai

Department of human, environmental andDepartment of human, environmental andnatural Sciences;natural Sciences;

Cytometry and Cytomorphology Center,Cytometry and Cytomorphology Center,University of Urbino;University of Urbino;

INFN LNGS Assergi, LAquilaINFN LNGS Assergi, LAquila


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Natural Killer CellsNatural Killer Cells

Site of generation:Site of generation: Bone marrow (lymph nodes ...)Bone marrow (lymph nodes ...) Morphology:Morphology:Large granular lymphocytesLarge granular lymphocytes

Phenotype:Phenotype:CD56CD56++, CD16, CD16++, CD161, CD161++, IL-2R, IL-2R,, TCRTCR--, sIg, sIg--;;

Inhibitory receptors : KIRInhibitory receptors : KIR++, CD94/NKG2A;, CD94/NKG2A;

Activatory receptors: NCRs, NKG2D, 2B4Activatory receptors: NCRs, NKG2D, 2B4

Function:Function:11..Cytotoxic activity mediated by lytic proteinCytotoxic activity mediated by lytic protein(perforin and granzymes) secretion or by(perforin and granzymes) secretion or bysurface molecules (FasL and TRAIL)surface molecules (FasL and TRAIL)without prior sensitization (vs. tumor andwithout prior sensitization (vs. tumor andvirus-infected cells)virus-infected cells)

22.. Cytokine secretion (IFN-Cytokine secretion (IFN-, TNF-, TNF-,,GM-CSF, IL-5 etc.)GM-CSF, IL-5 etc.)


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Cytokine secretion

TNF- GM-CSFIFN- IL-5

TRAIL (inducible)/TRAIL-Rs

Fas-L (inducible) /Fas

(Ca2+-independent)

Granule exocytosis

(Ca2+-dependent)

PerforinGranzymes

Target:

Necrosis

Apoptosis

Target:

Cytostasis

Differentiation

Death

Cytotoxic activity and cytokine production


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CD56dimcells are highly cytotoxic preferentially

express KIRs and CD16 (that mediate antiboby

dependent cell cytotoxicity, ADCC) and are

preferentially activated after target cell recognition

CD56brightcells produce high amounts of cytokines and

preferentially express CD94-NKG2A inhibitory

receptors and CD117 (c-kit), CD25 (IL-2 receptor alfa

chain), CD62L, CCR7 (lymph node homing receptor)

and are preferentially activated via cytokines (DC-

derived IL-15, IL-12 and T cell-derived IL-2)

Similar to CD8 and CD4 T cells, NK cells

can be divided in two different subsets


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Peripheral blood NK cell subsetsCD56dim

95% of PB NK cells

More mature?

highly cytotoxic


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Peripheral blood NK cell subsetsCD56bright

5% of PB NK cells,

are present in the

lymph nodes

more immature?


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NK Cell FunctionsNK Cell FunctionsNK and LAK (lymphokine activated killer)cells can kill via different mechanisms

NKR

NK cellfunctions areregulated byactivatoryandinhibitoryreceptors

(NKR)

NCRs,NKG2D


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NK cells express a lot NKdifferent activating receptors

Moretta L and A, EMBO,2004, 23, 255


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human NK cells engaged by theirhuman NK cells engaged by their

ligands on targetsligands on targets

Activation via ITAM induces Vav1 phosphorilation


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receptors are expressed byreceptors are expressed by

human NK cellshuman NK cells

Bryceson et al. (2006) Immunol. Rev.

ITIM recruit aphosphatase, SHP-1,

that dephosphorilatesVav1, blocking allactivatory pathways


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(lectin-like and(lectin-like and

immunoglobulin-like)immunoglobulin-like)

expressed on subsets of NKexpressed on subsets of NKcellscells

CD158eCD158

Killer Ig-likereceptors(KIRs) with 2 or 3

Ig-like domainsKIR2DL andKIR3DL

HeterodimericreceptorCD94/NKG2A,B

There are also

activating version

KIR2DS and KIR3DS

with a shortintracytoplasmic tail

There are also

activating version

CD94/NKG2C and E


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--receptors on human NK cells (KIR,receptors on human NK cells (KIR,

CD94/NKG2A) binds to different HLACD94/NKG2A) binds to different HLA

oligomorphic epitopesoligomorphic epitopes

CD158e

CD158b

CD158a

Recruitment of SHP-1 phosphatase via ITIM induces Vav1


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Activatory signals fromactivating receptors are

blocked by HLA class Iinhibitory receptors engaged

by self HLA molecules

Missing self recognition


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Missing self recognition of NK cells can

occur in haploidentical hematopoietic stem

cell transplantation

Velardi et al. 2008


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Selection of donor NK cells with donor versus

recipient alloreactivity improves haploidentical

hematopoietic stem cell transplantation

Moretta et al. 2009


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Selection of donor NK cells with donor

versus recipient alloreactivity :

involvement of activating KIR (KIR2DS1)


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MHC-IMHC-I

TCR-1

TCR-1

KIR

CD94/NKG2A

NO LYSIS

NO LYSIS

LYSIS

LYSIS

NKG2DNKG2D

NCRNCR

NCRNCR

NKG2DNKG2D

ULBPsMICA/B

ULBPs

MICA/B

Complementary role of T and NK cells inMHC-driven cell cytotoxicity: self-MHC-I

inhibits (NK), activates (T)

CD94/NKG2A

KIR


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NK cells act early during immune

response before the activation of CTLs

responsible for virus eradication


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Evidence of long lasting control of

some diseases performed by NK cells

depending on KIRs/HLA-I pairs

Some KIRs/HLA-I pairs protect from:

1) virus progression

2) tumor progression

Finally some KIRs-HLA-I pairs predispose to

autoimmunity


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killer immunoglobulin-like receptors

KIRs

recognize oligomorphic regions of HLA-I

molecule (KIR-ligand).

evolutively recent molecules

(mice do not expressed KIRs but lectin-like,

Ly49 molecules with similar function but

different structure)

probably specialized to fight new evolved

diseases (i.e. HIV)


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Evidences that some KIR/HLA-I

pairs give protection against virus

Cytomegalovirus (CMV)

Human immunodeficiency

virus (HIV) Hepatitis C virus (HCV)

Fi t id th t NK ll t t


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First evidence that NK cells protects

from virus (CMV) progression in mice


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Similar to CMV in mouse, an activatory

KIR give protection from AIDS

progression in humans


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Some KIR/HLA-I pairs protect from

AIDS progression


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Some KIR/HLA-I pairs protect from HIV

replication in vitro


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Some KIR/HLA-I pairs (KIR2DL3/HLA-

C1) protect from HCV progression

Intriguingly,KIR2DL3 has a

low affinity for its

ligand, HLA-C1


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And NK cells can recognize peptides on

HLA-C1

a possibility of a masking self recognition when a viral

peptide is mounted on HLA-I, in particular in KIR/HLA-I

pairs with low affinity binding (KIR2DL3/HLA-C1)


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Cervical neoplasia

Melanoma

Leukaemia

Evidences that some KIR/HLA-I

pairs give protection against tumor

progression


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Some KIR-HLA-I pairs give protection

from cervical neoplasia


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Some KIR-HLA-I pairs give protection

from malignant melanoma

Expansion of some NK (CD158a+) cells from


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Expansion of some NK (CD158a+) cells from

melanoma patients expressing the

corresponding HLA-C ligand, suggests their

involvement in the control of the disease

Some KIRs predispose to leukaemia


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Some KIRs predispose to leukaemia

development

May some other KIRs protect from leukaemia?


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NK cells and predisposition to

autoimmune diseases

Psoriatic ArthritisAnkylosing Spondylitis

DiabetesMultiple sclerosis

S KIR/HLA I i di t


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Some KIR/HLA-I pairs predispose to

psoriatic arthritis

Some KIR HLA I pairs predispose to


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Some KIR-HLA-I pairs predispose to

ankylosing spondylitis

Some KIR/HLA I pairs predispose to


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Some KIR/HLA-I pairs predispose to

diabetes

S KIR/HLA I i di t


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Some KIR/HLA-I pairs predispose to severe

Multiple sclerosis

Si il t T NK ll b


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Similar to T, NK cells can be

activated by DC

Moreover NK cells with


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Moreover . NK cells with

Memory function


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Memory NK cells

Fi ll NK ll ff t f


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Finally, NK cells as effectors of

vaccine-induced immunity


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Conclusions: in some cases NK cellsseems to do a job similar to CTLs

Depending on:

1) the disease (relatively new pathogens);

2) the HLA-I (KIR ligand and/or TcR ligand) and

3) the KIRs expressed by the subjects

it can be predisposed a NK cell:

1) immunosurveillance of viral-infected or cancer

cells 2) autoimmune response

A possible complementary role of T and NK

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Zamai GIC 2010 How NK Cells Influence Desease

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