Intravenous immunoglobulins promote skin allograft acceptance by triggering functional activation of CD4+Foxp3+ T cells

Background. Intravenous immunoglobulins (IVIg) therapy is effective as a treatment for T-cell-mediated immune diseases, but whether and how IVIg suppress allogeneic T-cell responses is largely unknown. Methods. In vitro, human CD4+, CD4+CD25+, or CD4+CD25 + T cells were stimulated with allogeneic antigen-presenting cells (APCs), and mouse CBA/Ca (H2k) CD4+ or CD4 +CD25+ T cells were stimulated with C57BL/10 (H2) splenocytes, in the presence or absence of IVIg. Proliferation, binding of IVIg, expression of activation markers, and ZAP70-phosphorylation were determined. In vivo, 1×105 CD4+ or CD4+CD25- T cells of CBA/Ca mice were adoptively transferred into CBA/RAG1-/- mice, which were 1 day later transplanted with skin grafts of C57BL/10 mice. IVIg was administered intravenously and skin graft survival was determined. Results. IVIg bound to the surface of human and mouse CD4+Foxp3 regulatory T cells (Tregs). IVIg binding resulted in functional activation of Tregs, as detected by increased expression of surface activation markers, enhanced ZAP70-phosphorylation, and increased capacity to suppress allogeneic T-cell proliferation. IVIg inhibited allogeneic T-cell proliferation in the presence of Tregs, but this effect was abrogated on selective depletion of CD25+ cells from responder T cells. IVIg prevented T-cell-mediated rejection of fully mismatched skin grafts in CBA/RAG1 mice reconstituted with CD4+ T cells, but this effect was lost on selective depletion of CD4+CD25+ cells from transferred T cells, indicating that IVIg induced dominant allograft protection mediated by Tregs. CONCLUSIONS.: Our data show that IVIg suppress allogeneic T-cell responses by direct activation of Tregs. IVIg treatment, which has been proven safe, may have therapeutic potential in tolerance-inducing strategies in transplant medicine.

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