Rapamycin enhances the number of alloantigen-induced human CD103+CD8+ regulatory T cells in vitro

Regulatory T cells (T(reg) cells) may be operational in both the induction and maintenance of transplantation tolerance. We recently showed that alloantigen-induced CD103+ CD8+ T cells strongly suppressed T-cell proliferation in mixed lymphocyte culture (MLC) via a contact-dependent mechanism. CD103 directs T lymphocytes to their ligand E-cadherin, which is expressed on renal tubular epithelial cells, and CD103+ CD8+ T cells have been described to be present in late renal allograft rejection. We studied the influence of prednisolone, cyclosporin, tacrolimus, CD25 monoclonal antibodies, rapamycin, and mycophenolate mofetil (MMF) on the development and functional activity of alloantigen-activated CD103+ CD8+ T cells in MLC. Calcineurin inhibitors, MMF, and CD25mAb did not influence the number of CD103 expressing CD8+ T cells. In contrast, corticosteroids diminished CD103 expression on alloactivated CD8+ T cells, which appeared to be caused by their inhibitory action on myeloid dendritic cells. Addition of rapamycin to allocultures led to an increased percentage of CD103+ CD8+ alloreactive T cells. Moreover, in the presence of rapamycin, these cells tended to show higher suppressive capacity. Alloreactive CD103+ CD8+ T(reg) cells may expand and exert their suppressive function during immunosuppressive treatment with rapamycin. These data are relevant in the design of immunosuppressive drug regimens intended to induce and/or maintain transplantation tolerance.