Contini Paola, Ghio Massimo, Poggi Alessandro, Filaci Gilberto, Indiveri Francesco, Ferrone Soldano, Puppo Francesco
Department of Internal Medicine (DIMI), University of Genova, Genova, Italy.
Eur J Immunol. 2003 Jan;33(1):125-34. doi: 10.1002/immu.200390015.
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 the activity 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.
有确凿证据表明，可溶性HLA-A、-B、-C（sHLA-A、-B、-C）和可溶性HLA-G（sHLA-G）抗原可诱导CD8(+)活化T细胞凋亡，尽管关于sHLA-A、-B、-C抗原和sHLA-G抗原诱导凋亡的机制的信息很少且相互矛盾。在本研究中，我们比较了sHLA-A、-B、-C抗原与sHLA-G1抗原在CD8(+) T淋巴细胞和CD8(+) NK细胞中的凋亡诱导能力。此外，我们还比较了sHLA-A、-B、-C抗原和sHLA-G1抗原对EBV特异性CD8(+)细胞毒性T淋巴细胞（CTL）活性的抑制作用。sHLA分子从血清以及用编码经典或非经典HLA I类抗原的单个基因转染的HLA I类阴性细胞的上清液中纯化得到。经典和非经典的sHLA I类分子均可在缺乏T细胞受体的CD8(+) T淋巴细胞和CD8(+) NK细胞中触发凋亡，且它们的凋亡效力相当。sHLA-A、-B、-C和sHLA-G1分子与CD8的结合导致Fas配体（FasL）上调、可溶性FasL（sFasL）分泌以及通过Fas/sFasL相互作用导致CD8(+)细胞凋亡。此外，经典和非经典的sHLA I类分子均抑制EBV特异性CD8(+) CTL的细胞毒性活性。由于在正常血清中可检测到的sHLA-G分子数量明显低于sHLA-A、-B、-C分子，从血清中纯化的sHLA I类分子的免疫调节作用可能主要归因于经典HLA I类抗原。就这些发现的潜在体内相关性而言，我们认为经典sHLA I类分子可能在以免疫系统激活和sHLA-A、-B、-C血清水平升高为特征的临床情况下发挥主要免疫调节作用。相比之下，非经典HLA I类分子可能在以sHLA-G水平升高为特征的特定条件下发挥免疫调节作用，如妊娠和某些肿瘤性疾病。
