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.

Cancer stem cell theory postulates that a small population of tumor-initiating cells is responsible for the development, progression and recurrence of several malignancies, including glioblastoma. In this perspective, tumor-initiating cells represent the most relevant target to obtain effective cancer treatment. Metformin, a first-line drug for type II diabetes, was reported to possess anticancer properties affecting the survival of cancer stem cells in breast cancer models. We report that metformin treatment reduced the proliferation rate of tumor-initiating cell-enriched cultures isolated from four human glioblastomas. Metformin also impairs tumor-initiating cell spherogenesis, indicating a direct effect on self-renewal mechanisms. Interestingly, analyzing by FACS the antiproliferative effects of metformin on CD133-expressing subpopulation, a component of glioblastoma cancer stem cells, a higher reduction of proliferation was observed as compared with CD133-negative cells, suggesting a certain degree of...

Alteration of T cell suppression function has been recognized in patients with systemic lupus erythematosus (SLE). Recently, CD8⁺ T suppressor lymphocytes (CD8⁺ Ts) have been generated in vitro by incubating purified CD8⁺ T cells with IL-2 and GM-CSF. Using this method, we generated CD8⁺ Ts from patients affected by SLE. No major differences were found in the CD8⁺ Ts phenotype between SLE patients and healthy subjects. CD8⁺ Ts from SLE patients with active disease did not inhibit the anti-CD3 mAb-induced proliferation of autologous PBMC, whereas CD8⁺ Ts from SLE patients in remission exerted an inhibitory activity comparable to normal subjects. The inhibitory effect of CD8⁺ Ts cells was neither mediated by cytotoxic activity nor by apoptosis induction. Two cytokines, IFN-γ and IL-6, were found to be responsible for the function of CD8⁺ Ts. In fact, counteraction of CD8⁺ Ts suppression activity was obtained by blocking IFN-γ with a specific Ab or by inhibiting CD8⁺ Ts-mediated IL-6 secretion by an antisense oligonucleotide. Interestingly, CD8⁺ Ts from SLE patients showed a peculiar cytokine pattern characterized by an impaired secretion of IL-6 and an increased secretion of IL-12. Thus, it appears that an altered balance between inhibitory (IL-6) and stimulatory (IL-12) cytokines might be responsible for the functional impairment of CD8⁺ Ts in SLE patients.