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Reminders

Reminders. Midterm test on Tuesday Review session Saturday 4-6 PM, here. Reading: Chapters 3, 5, 6, 8.13-8.15. Natural killer (NK) Cells a link between innate and adaptive immunity.

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Reminders

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  1. Reminders • Midterm test on Tuesday • Review session Saturday 4-6 PM, here. Reading: Chapters 3, 5, 6, 8.13-8.15

  2. Natural killer (NK) Cells a link between innate and adaptive immunity • NK cells do not require a thymus for their development but have several similarities to activated CD8 T cells. • They look like large lymphocytes and contain granules. • They are ready to kill target cells. • They kill using perforin. • They can rapidly produce cytokines upon ligand recognition. • They seem to be especially important in resistance to intracellular infections of viruses or bacteria.

  3. CD8 T cell mediated killing Killing involves the generation of pores in the plasma membrane of target cells and also the initiation of programmed cell death by different pathways Perforin is a pore forming protein found in the granules of activated, but not naïve, CD8 killer cells. (It is related to complement component C9.)

  4. One way that NK cells recognize their targets NK cells have hallmarks of a pre-activated killer cell. They kill rapidly when they detect targets, for example, antibody coated cells. In this case the cells are activated by a low affinity Fc receptor that recognizes clustered antibody decorating a cell surface.

  5. KILLS! CD8 killer CD8 CD8 NK Infected cell Infected cell Virus has downregulated MHC class I NK cells play an important role in "backing up" CD8 T cells

  6. Microbes often try to suppress antigen presentation Herpes Virus ICP-47 blocks TAP function Adenovirus E1A inhibits transcription of MHC class I genes E3 binds and retains class I molecules in the ER Cytomegalovirus US3 protein sequesters class I molecules in the ER US2 & US11 proteins “dislocates” class I molecules from the ER to cytoplasm HIV Vpu and Nef inhibit class I expression

  7. Non-classical Class I molecules (other non-classical proteins map outside of the MHC) The human MHC class I genes These are important molecules for presentation of peptides to CD8 T cells "classical"

  8. Figure 3-23 These are important NK inhibitory ligands These are important molecules for presentation of peptides to CD8 T cells

  9. Missing self recognition by NK cells • NK cells express together both inhibitory and stimulatory receptors. • Some stimulatory receptors see self molecules which are often stress-induced "non-classical" MHC class I-like molecules that are not polymorphic. • RAE, MICA • NK cells also express inhibitory receptors which see self MHC, both classical and some non-classical MHC molecules.

  10. The family of MHC class I-like molecules involved in NK recognition • MHC class Ia (HLA-A,B,C)-all nucleated cells • MHC class Ib (HLA-E,F,G)-selective expression and specialized antigen presentation • MICA,B,C,D, E no b2m, no peptide, stress-induced

  11. Figure 8-32

  12. MICA recognition - “Stress”

  13. Figure 8-29

  14. Figure 8-30

  15. NK receptors are coded in two loci One locus encodes the Ig like KIRs the other the C-type lectin like molecules. Stimulatory and inhibitory receptors are intermingled. NK receptors are highly polymorphic. Interestingly, NK cells appear to undergo a self-tolerance process when immature, i.e., they learn self.

  16. NK tolerance by the mother to the fetus MHC class I antigens are expressed at very low levels in embryonic tissue. HLA-G is highly expressed by the placenta, suppressing NK function.

  17. NK cells can kill healthy cells from histoincompatible individuals

  18. Early in an inflammatory reaction, NK cells are activated and can eliminate cells that downregulate MHC class I

  19. Figure 8-28

  20. NK cell recognition Concepts • NK cells are effector cells, not naïve. • Recognition • NK cells can recognize targets Fc receptor. • NK "missing self" recognition of cells that lose MHC class I expression • Missing self recognition is based on the presence of both inhibitory and activating receptors on NK cells. • The inhibitory receptor recognition of MHC class I is not affected by bound peptide. • Non-classical MHC class I molecules include non-polymorphic molecules that map to the MHC and elsewhere. Some of these class I-like molecules do not associate with beta2 microglobulin and are induced by cell "stresses" such as DNA damage. • NK receptors come in two families, Ig-like and C-type lectin like. Members of both families can be activating or inhibitory. • Ig-like and C-type lectin like NK receptors map to discreet clusters in the genome and are quite polymorphic. • NK cells must learn self when immature.

  21. Likely Topics on the exam: • T cell receptor proteins • T cell receptor genes • CD3 function • CD4 vs CD8 functions • MHC class I vs II functions • MHC class I and class II protein structure • MHC restriction and peptide binding • Interaction with microbes • CD8 killing • T cell development in thymus • positive and negative selection, AIRE • Bone marrow transplantation • Costimulation, B7, CD28 • Adjuvant • Crosspresentation of exogenous proteins by dendritic cells • Th1 vs Th2 CD4 effector cells • Cytokines • NK recognition and function • Non-classical MHC class I molecules

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