CD4⁺CD25⁺ T cells alloactivated ex vivo by IL-2 or IL-4 become potent alloantigen-specific inhibitors of rejection with different phenotypes, suggesting separate pathways of activation by Th1 and Th2 responses

摘要

CD4⁺CD25⁺Foxp3⁺ T cells are regulatory/ suppressor cells (Tregs) that include non-antigen (Ag)-specific as well as Ag-specific Tregs. How non-Ag-specific naive CD4⁺CD25⁺ Treg develop into specific Tregs is unknown. Here, we generated adaptive Tregs by culture of naive CD4⁺CD25⁺Foxp3⁺ T cells with allo-Ag and either interleukin-2 (IL-2) or IL-4. Within days, IL-2 enhanced interferon-γ receptor (Ifnγr) and Il-5 mRNA and IL-4 induced a reciprocal profile with de novo IL-5Rα and increased IFN-γ mRNA expression. Both IL-2- and IL-4-alloactivated CD4⁺CD25⁺ Tregs within 3 to 4 days of culture had enhanced capacity to induce tolerance to specific donor but not to third-party cardiac allografts. These hosts became tolerant as allografts functioned more than 250 days, with a physiologic ratio of less than 10% CD4⁺CD25⁺Foxp3⁺ T cells in the CD4⁺ population. CD4⁺CD25⁺ T cells from tolerant hosts given IL-2-cultured cells had increased Il-5 and Ifnγr mRNA. Those from hosts given IL-4-cultured cells had enhanced IL-5Rα mRNA expression and IL-5 enhanced their proliferation to donor but not third-party allo-Ag. Thus, IL-2 and IL-4 activated allo-Ag-specific Tregs with distinct phenotypes that were retained in vivo. These findings suggested that T-helper 1 (Th1) and Th2 responses activate 2 pathways of adaptive Ag-specific Tregs that mediate tolerance. We propose they be known as T-suppressor 1(Ts1)and Ts2 cells.