Zamai GIC 2010 How NK Cells Influence Desease
Transcript of 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