Natural killer cells

by MHCI

constitutive cytotoxicity of NK needs to be controlled

inhibitory NK receptor: with ITIM motif

one phosphorylable Y, phosphatase recruitment (SHP-1), contains SH2 domains (Src homology 2) docking onto phosphorylated tyrosine

activating NK receptor

ITAM = two phosphorylable Y, protein tyrosine kinase recruitment in cytoplasmic tail

most ligands self-ligands (not presented in context of MHC)

needs missing-self —>for activation less/no MHCI at surface (missing of MHCI)

random expression of inhibitory receptor specific for MHCI during development

• engagement of one unique inhibitory receptor is enough to keep the cell silent

• negative signaling is dominat

missing self

infected or transformed host MHC-negative

—>aquisition of genes inhibiting MHCI expression to evade T-cells but susceptible for NK cells

NK cells from WT mice don’t kill syngeneic splenocytes & kill splenocytes from ß2m deficient mice

NK cells from ß2m deficient mice don’t kill splenocytes from ß2m deficient mice—>cant kill without MHCI—>education needed

NK cell licensing during development

development from hematopoietic stem cells to be functional NK cell

needs interaction of MHCI & inhibitory receptors otherwise no full maturation

ADCC receptor

natural cytotoxicity receptor NCR

killer immunoglobulin-like receptor

immunoglobulin-like

C-type lectin

recurrent positive charge in the transmembrane domain to interact with an adaptor protein containing an ITAM

antibody-dependent cellular cytotoxicity

binds coated antibodies (IgG)

CD16

cytosolic ITAM motif induces NK cell killing of cell-bound IgGs on surface

• antibody binds antigen on surface of target cells

• Fc receptors on NK cells recognize bound antibody

• cross-linking of Fc receptors signals NK cells to kill the target cell

• target cell dies by apoptosis

NKp30/44/46

binds viral hemagglutinin or calreticulin on stressed cells

KIR

binds HLA-C (classical)/F (non-classical) (recognizes MHCI origin)

ubiquitous expressed ligand

DNAM-1

binds nectin

ubiquitous expressed ligand

CD94/ NK2-C heterodimer binds HLA-E (recognition of non-classical MHC instead of sugar)

NKG2-D homodimer binds MIC(MHCI like)

stress-induced ligands self-expressed but not under normal conditions

KIR (killer immunoglobulin-like receptor)

long form = KIR(XD)L contains ITIM

short form = KIR(XD)S contains a positive charge

can have same extracellular domain but not the same gene (sequence differences)—>group 1 & 2

different cytosolic domains —> L or S

KIR2DS2 recognizes HLA-C with conserved peptides from flavivirus (dengue, zika, yellow fever)

C-type lectin also inhibitory (ITIM) or activating intracellular domains (positive charge)

MHCI important, depending on receptor activation or inactivation

two phosphorylable T, kinase recruitment

activating

one phosphorylable Y, phosphatase recruitment

no KIR receptors —>not always good model (developed after separation of mouse & human)

only C-type lectins (Ly49 family)

also specific for MHC alleles in mouse H2-K/-D/-L

homodimers

also either inhibitory or activating forms

TCR/MHC interaction at topside of α & ß chain of TCR

interacts with hypervariable loop

interaction KIR/MHC more flexible binding—>no peptide specificity

derive from hematopoietic stem cell in bone marrow

then to common lymphoid progenitor

differentiation not known

results in innate lymphoid cells

NK part of ILC1 (can produce IFNγ)

different intensites of CD56 expression (marker NK cells)

also present on some T-cells (pan T-cell marker CD3 against TCR) negative and CD56 positive

2 populations CD56 bright & dim

expresses CD16

may be precursors of CD56dim cells

appear first after HSC transplantation

immaturity marker CD117

longer telomers

phenotypically different cells (more differences by GEP than between blood CD56bright and CD56dim)

final differentiation for CD56bright induced by the environment—>depending on tissue different receptors

in contrast to T-cells no differentiation needed—>constitutive missing self killing

soluble components

—> perforin: inserts in membrane & creates pores

—>granzyme: enters cytoplasm & starts signaling for apoptosis

membrane receptors:

—>FAS ligand (binds to FAS that has a cytoplasmic death domain—>proapoptotic, TNF like superfamily)

—>TRAIL (binds 5 receptors, 3 inhibit apoptosis (no death domain), 2 with death domain)

no/less cytotoxicity

no inhibitory receptors

more cytokine production IFNγ/TNF

IL-2/IL-12 stimulation induces cytotoxicity

tissue-resident

circulating in the blodd

in decidua: more than 60% of lymphocytes

upon stromal cell and trophoblast recognition by NKp receptors

• secretion of chemotactic factors for trophoblast invasion

• secretion of proangiogenic factors

pregnancy allotransplantation of the mother, fetus feeds from mother—>arteries enter

NK don’t mediate killing but release of GF

genetically identical, or sufficiently identical and immunologically compatible as to allow for transplantation

twins

Genetically distinct, but of the same species

different MHC complex

derived from another species

tissue-resident, not cytotoxic

activated DC produces pro-inflammatory cytokines (IL-12) stimulating NK cells

activated NK cells produce IFNγ and promote TH1 type immunity

in lymphoid tissues

role of NK in adaptive immunity induction

Patient 3

random expression of KIR in donor: L3/L1 or L!&L3

dominant negative effect

education by MHCI needed