Nk cells
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NK cells. Large granular lymphocytes ~5-15% human peripheral blood lymphocytes ~2-3% mouse spleen cells “non-specific” cytotoxicity standard targets K562 for human YAC-1 for mouse Cytokine production (IFN g, TNF a etc.)

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NK cells

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Nk cells

NK cells

  • Large granular lymphocytes

  • ~5-15% human peripheral blood lymphocytes

  • ~2-3% mouse spleen cells

  • “non-specific” cytotoxicity

  • standard targets K562 for human

  • YAC-1 for mouse

  • Cytokine production (IFNg, TNFa etc.)

  • CD56+CD3- CD16+ (human)

  • NK1.1+CD3- (mouse)


Cytotoxic t cells and nk cells

Antigen specific

MHC-restricted

Requires priming

(takes days to respond)

Memory

Antigen non-specific

MHC non-restricted

Priming not required

(rapid response, hours)

No memory

Cytotoxic T cells and NK cells

Cytotoxic T cells

NK cells


Various ways nk cells kill target cells

Various ways NK cells kill target cells

TRAIL

(TNF-Related

Apoptosis-

Inducing Ligand)

ADCC

(Antibody Dependent

Cell Mediated

Cytotoxicity)

TNFa

Direct

cytotoxicity

NK

NK

NK

NK

CD16

target

target

target

target


Killing perforins granzymes

Killing: Perforins & Granzymes

CTL or NK Cell

granules contain perforin

and granzymes.

granzymes

perforins

+Ca++

Endocytosis

Storage

Vesicle

Movement along actin/

microtubule fibers.

Nucleus

Osmotic

Lysis

Cleavage

& activation

of caspases.

Apoptosis!

Transport of Gra B

to nucleus.


Mhc class i

MHC class I

MHC is used as a marker for self vs non-self by the immune system.


Recognition of foreign vs self by cytotoxic t cells

Recognition of foreign vs self by cytotoxic T cells

Cytotoxic T cell

T cells recognize ‘foreign’.

kill

peptide

MHC

cell

Self MHC +

foreign peptide

foreign MHC +

foreign peptide

Self MHC +

self peptide

No MHC


Recognition of foreign vs self by nk cells

Recognition of foreign vs self by NK cells

NK cell

NK cells recognize non-self

(missing self)

kill

peptide

MHC

cell

Self MHC +

foreign peptide

foreign MHC +

foreign peptide

Self MHC +

self peptide

No MHC


Mhc class i specific inhibitory receptors on nk cells

MHC class I-specific inhibitory receptors on NK cells

NK cell

No

activation

activation

activation

Inhibitory

receptor

Activation

receptor

Foreign

MHC

Self-

MHC

No

MHC


Inhibitory receptors on nk cells signaling

Inhibitory receptors on NK cells:signaling

ITIM

(Immunoreceptor Tyrosine-based

Inhibitory Motif)

Inhibitory receptor

p

p

Activation

receptor

SHP1

phosphatase

Src-family

kinases

dephosphorylation


Nk cells recognition of self vs non self

NK cells: recognition of self vs non-self

MHC +ve

MHC -ve

Eriksson et al. J Exp Med 190:1005, 1999

NK cells recognize self-MHC class I.


Nk cells

NK cell receptors for MHC class I

LIR (ILT)-1

KIR

(>13)

CD94/NKG2

(4)

Lectin-

like

family

Human

Immunoglobulin

family

Ly-49

(>10)

CD94/NKG2

(3)

Mouse


Human nk receptors kir killer immunoglobulin like receptors

Human NK receptors: KIR (killer immunoglobulin-like receptors)

2DL

2DS

2DL4

3DL

3DS


Human nk cell receptors for hla

Human NK cell receptors for HLA


Mouse nk receptors for mhc class i

H

Mouse NK receptors for MHC class I

Non-classical MHC class I Qa-1b

peptide

Classical MHC class I (H-2Dd, Kb etc.)

Ly49 family

CD94/NKG2

A C E

A

C

D

E

F

G

I

J


Mhc class i specificity of ly49

MHC class I specificity of Ly49

Ly49

MHC class I

A B C D E F GH I J

Dd, Dk

??

Kb, Kk, Kd, Dd, Db, Dk

Dd

?

H-2d ?

Dd

?

Kb, Kd ?

?


Co expression of multiple receptors on individual nk cells

Ly49A

Ly49B

Ly49C

Ly49D

Ly49E

Ly49F

Ly49G

Ly49H

Ly49I

Ly49J

1

10

20

30

40

50

60

70

80

CD94

NKG2A

NKG2C

NKG2E

Co-expression of multiple receptors on individual NK cells

  • NK cells are very heterogenous  can recognize different targets.

  • Most NK cells express at least one receptor specific for self MHC class I  maintain self-tolerance.


Nk cell activating receptors

NK cell activating receptors

We know much about inhibitory receptors on NK cells, but

how about activating receptors?

Ly49D, H

?

More activating receptors are to be found.


Nk cells inhibit growth of tumors expressing nkg2d ligands

NK cells inhibit growth of tumors expressing NKG2D ligands

Tumor growth in mice

Lung metastasis of melanoma

From Nature 413: 165, 2001

Diefenbech et al.


Diversity of human nk receptors kirs

Diversity of human NK receptors KIRs

Haplotype diversity and allelic polymorphism

Almost everybody differs from each other in KIRs.

All NK cells express at least one inhibitory receptor for self MHC.


Bone marrow cell transplantation and nk cells graft versus leukemia without gvh

Bone marrow cell transplantation and NK cells: graft versus leukemia without GVH ?

Science 295:2097, 2002

In HLA-mismatched bone marrow transplantation, some donor-derived

NK cells are not inhibited by host HLA and kill leukemia cells expressing host HLA.

Donor NK cells also kill host antigen presenting cells and prevent GVHD.


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