1. January 21, 2009 Penny Morel morel@pitt.edu, 4-0343
Natural Killer Cells
January 21, 2009
Penny Morel

2. Innate capacity of lysis Large granular lymphocytes
CD3-, CD16+, CD56+, CD122+, CD158+, CD161+ 2

5. NK Cell Differentiation
Derive from, and require normal, intact bone marrow for functional maturation
Represent one of the major lymphocyte populations [T, B, NK, NK-T] – ~5% of cells among PBLs
Present in athymic [nude] mice and rats
Present in scid mice, and in RAG-1 and RAG-2 knockout mice
Can be distinguished from other lymphocytes by the absence of clonally distributed, receptors derived via gene rearrangements

6. NK Progenitors: Adult . . . Bone marrow Thymus NK NK HSC CLP NKP p-NK
stroma NK . NK .
HSC
CLP
NKP
p-NK
Lin-
c-kitlo
Thy-1-
IL7R+
Sca-1lo
CD122+
CD161c+
CD49b-
CD122+
CD161c+
CD49b+
Ly49+
CD122+
CD161c+
CD49b+
Ly49+
CD122+
CD161c-
CD49b-
Thymus
p-NK NK .
p-T/NK
p-T T T
Modified from Lian and Kumar, 2002 6

7. Annual Review of Immunology
Vol. 22:

8. Transcription factors and cytokines necessary for NK cell
development
Annual Review of Immunology
Vol. 22:

9. NK Cell Recognition Receptors
“Missing Self” Hypothesis
Activation and Inhibition via Receptors
Recognition of “Self”
Recognition of Tumor Cells
Recognition of Virus-infected Cells 9

10. Recognition – NK cells
There is no evidence supporting clonally restricted recognition molecules expressed by NK cells, nor for recombinatorial events being important for development of an NK cell repertoire
NK cells recognize MHC determinants, but neither these structures, nor peptides expressed by MHC, are target antigens for activation of NK lytic function
Some NK cells express CD8 homodimers, but it is unclear whether binding to MHC Class I affects activation
NK cell recognition of targets involves a balance between inhibitory signals and activation signals
Receptor:ligand pairs providing inhibitory signals are fairly well defined
Receptor:ligand pairs providing activation signals are rapidly being defined 10

13. Raulet et al. Nature Reviews Immunology 6, 520–531 (July 2006) | doi:10.1038/nri1863

14. Raulet et al. Nature Reviews Immunology 6, 520–531 (July 2006) | doi:10.1038/nri1863

17. ITIM Immunoreceptor tyrosine-based inhibitory motif
Based upon the amino acid motif: I/VxYxxL
Commonly expressed in signaling receptors in lymphocytes
Recruits SHP-1/SHP-2 phosphatases
Linked to inhibition of function in lymphocytes 17

21. ITAM Immunoreceptor tyrosine-based activating motif
Based upon the amino acid motif: …YxxL/Ix6-8YxxL/I…
Serves as a signaling partner to transmembrane receptors with a charged residue in the transmembrane region which allows docking of signal transducers such as DAP12, CD3z-CD3z homodimers, CD3z-Fcer1g heterodimers
Activation of cells either via PI3 kinase, or ZAP70 or Syk tyrosine kinases 21

22. Current Opinion in Immunology
Volume 19, Issue 1, February 2007, Pages 46-5

23. NK development - questions
Many NK cells express multiple inhibitory receptors
Many of these receptors do not have specificity for self MHC
What is the purpose of these receptors?
How are NK cells self tolerant?
MHC class I KO mice have normal NK cells that do not kill these cells - why?

24. Nature Immunology 5, (2004)

25. Raulet et al. Nature Reviews Immunology 6, 520–531 (July 2006) | doi:10.1038/nri1863

26. NKG2D Single gene Distantly related to other NKG2 family members
Alternatively spliced isoforms (short and long) in mice
NKG2D-s and NKG2D-l, short from binds both DAP10 and DAP12
Expressed in NK cells, CD8+ cells and macrophages 26

27. Nature Reviews Immunology 3, 781-790 (October 2003)

28. Nature Reviews Immunology 3, 781-790 (October 2003)

29. Nature Reviews Immunology 3, 781-790 (October 2003)

30. Immunological Reviews
Volume 214, Issue 1, Pages

37. Nature Immunology 5, (2004)

38. Nature Reviews Immunology 3, 781-790 (October 2003)