Soluble HLA‐A,‐B,‐C and ‐G molecules induce apoptosis in T and NK CD8+ cells and inhibit cytotoxic T cell activity through CD8 ligation

Abstract

There is convincing evidence that soluble HLA‐A,‐B,‐C (sHLA‐A,‐B,‐C) and soluble HLA‐G (sHLA‐G) antigens can induce apoptosis in CD8+ activated T cells although there is scanty and conflicting information about the mechanism(s) by which sHLA‐A,‐B,‐C antigens and sHLA‐G antigens induce apoptosis. In this study we have compared the apoptosis‐inducing ability of sHLA‐A,‐B,‐C antigens with that of sHLA‐G1 antigens in CD8+ T lymphocytes and CD8+ NK cells. Furthermore we have compared the inhibitory effect of sHLA‐A,‐B,‐C antigens and of sHLA‐G1 antigens on theactivity of EBV‐specific CD8+ cytotoxic T lymphocytes (CTL). sHLA molecules were purified from serum and from the supernatant of HLA class I‐negative cells transfected with one gene encoding either classical or non‐classical HLA class I antigens. Both classical and non‐classical sHLA class I molecules trigger apoptosis in CD8+ T lymphocytes and in CD8+ NK cells, which lack the T cell receptor, and their apoptotic potency is comparable. The binding of sHLA‐A,‐B,‐C and sHLA‐G1 molecules to CD8 leads to Fas ligand (FasL) up‐regulation, soluble FasL (sFasL) secretion and CD8+ cell apoptosis by Fas/sFasL interaction. Moreover, classical and non‐classical sHLA class I molecules inhibit the cytotoxic activity of EBV‐specific CD8+ CTL. As the amount ofsHLA‐G molecules detectable in normal serum is significantly lower than that of sHLA‐A,‐B,‐C molecules, the immunomodulatory effects of sHLA class I molecules purified from serum are likely to be mainly attributable to classical HLA class I antigens. As far as the potential in vivo relevance of these findings is concerned, we suggest that classical sHLA class I molecules may play a major immunoregulatory role in clinical situations characterized by activation of the immune system and elevated sHLA‐A,‐B,‐C serum levels. In contrast, non‐classical HLA class I molecules may exert immunomodulatory effects in particular conditions characterized by elevated sHLA‐G levels such as pregnancy and some neoplastic diseases.