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 gamma delta T cells express several NKRs. Expression of these receptors is confined to the cytolytic V delta 2 subset, which coexpresses the Fc gamma RIII CD16 and CD45RA and has been defined as V gamma 9V delta 2 T-EMRA cells. We show that the CD94/NKG2C complex, associated with KARAP/DAP12, is fully functional in gamma delta T cells, as determined by measuring IFN-gamma production, T cell proliferation, and cytolytic activity by gamma delta lymphocytes. In contrast, NKG2A expression was found on all gamma delta T cell memory subsets, suggesting a crucial role of the inhibitory signal provided by this receptor on gamma delta T cell responses. Moreover, we found V gamma 9V delta 2 T-EMRA, NK, and CD8(+) alpha beta 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 gamma delta 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 gamma delta cells in LDGL patients is a result of effective inhibitory HLA class I receptors. J. Leukoc. Biol. 89: 75-84; 2011.