6/7/17. Immune cells. Co-evolution of innate and adaptive immunity. Importance of NK cells. Cells of innate(?) immune response

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1 Immune cells Co-evolution of innate and adaptive immunity 1 2 Importance of NK cells Cells of innate(?) immune response Patients with NK cell deficiency may lead to fatal infections and have an increased risk of developing cancer particularly: highly susceptible to herpes infections Large granular cells Release cytotoxic proteins (perforin, and granzyme) induce apoptosis and death of virus infected and cancer cells maintain inflammation Associations between NK cell receptors and the disease outcome in HIV, HCV, and cerebral malaria

2 NK cells circulate between blood and tissues Belong to the lymphocyte lineage Early stages of development occurs in the bone marrow Do not express antigen-specific receptors (receptors do not undergo gene rearrangement) NK cells circulate in the blood, enter tissues and are present in the lymph vessels Act very fast upon infection "ready-to go" state 5 NK show tissue-specific characteristics (adapting their effector/inflammation capacities to the environment) 6 How can an NK cell distinguish healthy from unhealthy cells? How can an NK cell distinguish healthy from unhealthy cells? Main ligands for inhibitory NK cell receptors: MHC class I distinguish healthy tissue Main ligands for inhibitory NK cell receptors: MHC class I distinguish healthy tissue Viruses downregulate the MHC expression No inhibition, NK cells detects the infection "missing-self" detection 7 8 2

3 How can an NK cell distinguish healthy from unhealthy tissue? How do NK cells detect "missing-self"? Two receptor families Main ligands for activating NK cell receptors: molecules that are upregulated upon stress extra activating signal, NK cell detects the infection 9 CD94:NKG2 Family 10 Killer Immunoglobulin-like receptors HLA-E conserved MHC-class I, which presents peptides coming from HLA-A, HLA-B, and HLA-C KIR bind to the polymorphic site of the MHC molecule KIR are polygenic and polymorphic Inhibitory NKG2A binds to HLA-E HLA-E + NKG2A monitor the expression of the other HLA molecules KIR bind to HLA-A, -B, and -C (also highly polymorphic) Variable feature of the immune system Conserved feature of the human immune system

4 Killer Immunoglobulin-like receptors Stochastic Receptor Expression KIRs bind to the polymorphic site of the MHC molecule Sequential acquisition of receptors is random NK cell subsets having an stochastic receptor expression KIRs footprint overlaps with the TCR binding site KIRs are specific 13 NK cell education 14 Recap I In the bone marrow NK cells interact with MHC class I NK cells: Don't have antigen-specific receptors made via VDJ recombination+ Respond very fast upon infection à belong to innate immune response?? Detect "missing-self" Two main receptor families that help them distinguish self from non-self Receptor expression is stochastic and determined during NK cell development, giving rise to several functionally different phenotypes of NK cells

5 Uterine NK cells Uterine NK cells unk cells interact with fetal extravillous trophoblast cells to provide the placenta with adequate blood supply 18 Uterine NK cells 19 Recap II Shallow trophoblast invasion results in pre-enclampsia NK cells: Don't have antigen-specific receptors made via VDJ recombination+ Respond very fast upon infection à belong to innate immune response?? Too deep placental invasion causes the development of too large babies for the birth canal, and thus obstructed labor Detect "missing-self" Two main receptor families that help them distinguish self from non-self Receptor expression is stochastic, giving rise to several functionally different phenotypes of NK cells Cooperate with fetal trophoblasts in remodeling the uterine blood vessels, ensuring a proper nourishment for the fetus contribute to reproductive success

6 Self study: Rest of Chapter Theoretical Biology & Bioinformatics Can Kesmir 6