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Natural Killer Cells January 21, 2009 Penny Morel [email protected], 4-0343 Innate capacity of lysis Large granular lymphocytes CD3-, CD16+, CD56+, CD122+, CD158+, CD161+ 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 NK Progenitors: Adult Bone marrow stroma HSC CLP NKP p-NK Linc-kitlo Thy-1IL7R+ Sca-1lo CD122+ CD161cCD49b- CD122+ CD161c+ CD49b- . . .. .. NK NK .. CD122+ CD161c+ CD49b+ Ly49+ CD122+ CD161c+ CD49b+ Ly49+ Thymus . . .. p-NK NK p-T T p-T/NK Modified from Lian and Kumar, 2002 T Annual Review of Immunology Vol. 22: 405-429 Transcription factors and cytokines necessary for NK cell development Annual Review of Immunology Vol. 22: 405-429 NK Cell Recognition Receptors • • • • • “Missing Self” Hypothesis Activation and Inhibition via Receptors Recognition of “Self” Recognition of Tumor Cells Recognition of Virus-infected Cells 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 Raulet et al. Nature Reviews Immunology 6, 520–531 (July 2006) | doi:10.1038/nri1863 Raulet et al. Nature Reviews Immunology 6, 520–531 (July 2006) | doi:10.1038/nri1863 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 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 Current Opinion in Immunology Volume 19, Issue 1, February 2007, Pages 46-5 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? Nature Immunology 5, 996 - 1002 (2004) Raulet et al. Nature Reviews Immunology 6, 520–531 (July 2006) | doi:10.1038/nri1863 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 Nature Reviews Immunology 3, 781-790 (October 2003) Nature Reviews Immunology 3, 781-790 (October 2003) Nature Reviews Immunology 3, 781-790 (October 2003) Immunological Reviews Volume 214, Issue 1, Pages 130-142 Nature Immunology 5, 996 - 1002 (2004) Nature Reviews Immunology 3, 781-790 (October 2003)
