Control of self-reactive cytotoxic T lymphocytes expressing gamma delta T cell receptors by natural killer inhibitory receptors.
The majority of peripheral blood gamma delta T cells in human adults expresses T cell receptors (TCR) with identical V regions (V gamma 9 and V delta 2). These V gamma 9 V delta 2 T cells recognize the major histocompatibility complex (MHC) class I-deficient B cell line Daudi and broadly distributed nonpeptidic antigens present in bacteria and parasites. Here we show that unlike alpha beta or V gamma 9- gamma delta T cells, the majority of V gamma 9V delta 2 T cells harbor natural killer inhibitory receptors (KIR) (mainly CD94/NKG2A heterodimers), which are known to deliver inhibitory signals upon interaction with MHC class I molecules. Within V gamma 9V delta 2 T cells, KIR were mainly expressed by clones exhibiting a strong lytic activity against Daudi cells. In stark contrast, almost all V gamma 9V delta 2 T cell clones devoid of killing activity were KIR-, thus suggesting a coordinate acquisition of KIR and cytotoxic activity within V gamma 9V delta 2 T cells. In functional terms, KIR inhibited lysis of MHC class I-positive tumor B cell lines by V gamma 9V delta 2 cytotoxic T lymphocytes (CTL) and raised their threshold of activation by microbial antigens presented by MHC class I-positive cells. Furthermore, masking KIR or MHC class I molecules revealed a TCR-dependent recognition by V gamma 9V delta 2 CTL of ligands expressed by activated T lymphocytes, including the effector cells themselves. Taken together, these results suggest a general implication of V gamma 9V delta 2 T cells in immune response regulation and a central role of KIR in the control of self-reactive gamma delta CTL.
Halary
F
F
INSERM U463, Institute de Biologie, Nantes, France.
Peyrat
M A
MA
Champagne
E
E
Lopez-Botet
M
M
Moretta
A
A
Moretta
L
L
Vié
H
H
Fournié
J J
JJ
Bonneville
M
M
D000328:Adult; D002051:Burkitt Lymphoma; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006680:HLA Antigens / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000502:physiology; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D004915:Leukemia, Erythroblastic, Acute; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D009101:Multiple Myeloma; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000096:biosynthesis* / Q000502:physiology; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D054340:Receptors, KIR; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011971:Receptors, Immunologic; D054340:Receptors, KIR