NKG2A inhibits NKG2C effector functions of γδ T cells: implications in health and disease.
The CD94/NKG2 complex is expressed on T and NK lymphocytes. CD94 molecules covalently associate to activating or inhibitory NKG2 molecules, and their expression finely tunes cell responses. Human γδ T cells express several NKRs. Expression of these receptors is confined to the cytolytic Vδ2 subset, which coexpresses the FcγRIII CD16 and CD45RA and has been defined as Vγ9Vδ2 T(EMRA) cells. We show that the CD94/NKG2C complex, associated with KARAP/DAP12, is fully functional in γδ T cells, as determined by measuring IFN-γ production, T cell proliferation, and cytolytic activity by γδ lymphocytes. In contrast, NKG2A expression was found on all γδ T cell memory subsets, suggesting a crucial role of the inhibitory signal provided by this receptor on γδ T cell responses. Moreover, we found Vγ9Vδ2 T(EMRA), NK, and CD8+ αβ T cells coexpressing NKG2A and NKG2C receptors. Functional experiments showed that the inhibitory signal mediated by the NKG2A receptor prevails when double-positive cells are activated. Finally, NKG2A expression on γδ LDGL correlates with asymptomatic pathology, even in the presence of NKG2C coexpression, whereas in symptomatic patients affected by severe disease, the inhibitory NKG2A receptor is absent, and a variety of activatory NKRs was found. We propose that the silent behavior of γδ cells in LDGL patients is a result of effective inhibitory HLA class I receptors.
Angelini
Daniela F
DF
Neuroimmunology Unit, Fondazione Santa Lucia, Scientific Institute (I.R.C.C.S.), Rome, Italy.
Zambello
Renato
R
Galandrini
Ricciarda
R
Diamantini
Adamo
A
Placido
Roberta
R
Micucci
Federica
F
Poccia
Fabrizio
F
Semenzato
Giuseppe
G
Borsellino
Giovanna
G
Santoni
Angela
A
Battistini
Luca
L
D000818:Animals; D002999:Clone Cells; D003432:Cross-Linking Reagents / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006262:Health; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D054066:Leukemia, Large Granular Lymphocytic / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000276:immunology*; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000276:immunology; D010641:Phenotype; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014019:Tissue Donors
D003432:Cross-Linking Reagents; C527054:KLRC1 protein, human; C527059:KLRC2 protein, human; C497869:KLRD1 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D016692:Receptors, Antigen, T-Cell, gamma-delta