Licensing of natural killer cells by host major histocompatibility complex class I molecules.
Self versus non-self discrimination is a central theme in biology from plants to vertebrates, and is particularly relevant for lymphocytes that express receptors capable of recognizing self-tissues and foreign invaders. Comprising the third largest lymphocyte population, natural killer (NK) cells recognize and kill cellular targets and produce pro-inflammatory cytokines. These potentially self-destructive effector functions can be controlled by inhibitory receptors for the polymorphic major histocompatibility complex (MHC) class I molecules that are ubiquitously expressed on target cells. However, inhibitory receptors are not uniformly expressed on NK cells, and are germline-encoded by a set of polymorphic genes that segregate independently from MHC genes. Therefore, how NK-cell self-tolerance arises in vivo is poorly understood. Here we demonstrate that NK cells acquire functional competence through 'licensing' by self-MHC molecules. Licensing involves a positive role for MHC-specific inhibitory receptors and requires the cytoplasmic inhibitory motif originally identified in effector responses. This process results in two types of self-tolerant NK cells--licensed or unlicensed--and may provide new insights for exploiting NK cells in immunotherapy. This self-tolerance mechanism may be more broadly applicable within the vertebrate immune system because related germline-encoded inhibitory receptors are widely expressed on other immune cells.
Kim
Sungjin
S
Howard Hughes Medical Institute, Rheumatology Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Poursine-Laurent
Jennifer
J
Truscott
Steven M
SM
Lybarger
Lonnie
L
Song
Yun-Jeong
YJ
Yang
Liping
L
French
Anthony R
AR
Sunwoo
John B
JB
Lemieux
Suzanne
S
Hansen
Ted H
TH
Yokoyama
Wayne M
WM
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D003593:Cytoplasm; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D009154:Mutation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism
D001324:Autoantigens; D015395:Histocompatibility Antigens Class I; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D007371:Interferon-gamma; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse