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

6. 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 Microbes often try to suppress antigen presentation

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

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 1.MHC class Ia (HLA-A,B,C)-all nucleated cells 2.MHC class Ib (HLA-E,F,G)-selective expression and specialized antigen presentation 3.MICA,B,C,D, E no  2m, no peptide, stress-induced

11. Figure 8-32

12. MICA recognition - “Stress”

15. Figure 8-29

16. Figure 8-30

17. 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.

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

19. NK cells can kill healthy cells from histoincompatible individuals

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

21. Figure 8-28

22. 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.

23. 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