CTLA-4·FasL inhibits allogeneic responses in vivo

• Published in: Cellular immunology 2006-02, Vol.239 (2), p.129-135
• Main Authors: Dranitzki-Elhalel, M., Huang, J.-H., Rachmilewitz, J., Pappo, O., Parnas, M., Schmidt, W., Tykocinski, M.L.
• Format: Article
• Language: English
• Subjects: Activation-induced cell death (AICD); CD4+ T cells; CD8+ T cells; In vivo mixed lymphocyte reaction; Inhibition of alloresponse; Trans signal converter protein (TSCP)
• ISSN: 0008-8749; 1090-2163
• DOI: 10.1016/j.cellimm.2006.05.002

CTLA-4·Fas ligand (CTLA-4·FasL), a paradigmatic ‘trans signal converter protein (TSCP)’, can attach to APC (via CTLA-4 binding to B7) and direct intercellular inhibitory signals to responding T cells (via FasL binding to Fas receptor), converting an activating APC-to-T cell signal into an inhibitory one. Our previous studies established that CTLA-4·FasL inhibits human primary mixed lymphocyte reactions (MLR) and induces alloantigen-specific hyporesponsiveness ex vivo. The present study extends this to an in vivo context. Using splenocytes from MHC-mismatched C57BL/6 and Balb/c mice, we demonstrated that his6CTLA-4·FasL, effectively inhibits murine MLR. Moving in vivo, we demonstrated that subcutaneously administered his6CTLA-4·FasL modulates the in vivo response of infused allogeneic splenocytes. his6CTLA-4·FasL reduces the number of cells in each cell division, and increases the percentage of dead cells in each division. These findings are consistent with an antigen-induced cell death of the alloreactive cells, and bolsters recombinant TCSP promise as a therapeutic for transplantation diseases.