Natural Killer Cells

January 21, 2009

Penny Morel

morel@pitt.edu, 4-0343

Innate capacity of lysisLarge granular lymphocytesCD3-, 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

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+

Annual Review of ImmunologyVol. 22: 405-429

Annual Review of ImmunologyVol. 22: 405-429

Transcription factors and cytokines necessary for NK cell development

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, CD3-CD3 homodimers, CD3-Fcr1 heterodimers

• Activation of cells either via PI3 kinase, or ZAP70 or Syk tyrosine kinases

Current Opinion in ImmunologyVolume 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 ReviewsVolume 214, Issue 1, Pages 130-142

Nature Immunology 5, 996 - 1002 (2004)

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