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Innate capacity of lysisLarge granular lymphocytesCD3-, CD16+, CD56+, CD122+, CD158+, CD161+
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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
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NK Progenitors: Adult
NK .. ..HSC CLP NKP p-NK NK .. ..Lin-
c-kitlo
Thy-1-
IL7R+
Sca-1lo
CD122+
CD161c-
CD49b-
CD122+
CD161c+
CD49b-
CD122+
CD161c+
CD49b+
Ly49+
Bone marrowstroma
Modified from Lian and Kumar, 2002
p-T/NK
p-NK
p-T
NK .. ..
TT
Thymus
CD122+
CD161c+
CD49b+
Ly49+
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Annual Review of ImmunologyVol. 22: 405-429
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Annual Review of ImmunologyVol. 22: 405-429
Transcription factors and cytokines necessary for NK cell development
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NK Cell Recognition Receptors
• “Missing Self” Hypothesis
• Activation and Inhibition via Receptors
• Recognition of “Self”
• Recognition of Tumor Cells
• Recognition of Virus-infected Cells
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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
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Raulet et al. Nature Reviews Immunology 6, 520–531 (July 2006) | doi:10.1038/nri1863
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Raulet et al. Nature Reviews Immunology 6, 520–531 (July 2006) | doi:10.1038/nri1863
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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
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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, CD3-CD3 homodimers, CD3-Fcr1 heterodimers
• Activation of cells either via PI3 kinase, or ZAP70 or Syk tyrosine kinases
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Current Opinion in ImmunologyVolume 19, Issue 1, February 2007, Pages 46-5
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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?
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Nature Immunology 5, 996 - 1002 (2004)
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Raulet et al. Nature Reviews Immunology 6, 520–531 (July 2006) | doi:10.1038/nri1863
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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
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Nature Reviews Immunology 3, 781-790 (October 2003)
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Nature Reviews Immunology 3, 781-790 (October 2003)
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Nature Reviews Immunology 3, 781-790 (October 2003)
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Immunological ReviewsVolume 214, Issue 1, Pages 130-142
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Nature Immunology 5, 996 - 1002 (2004)
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Nature Reviews Immunology 3, 781-790 (October 2003)