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Transcript
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)