Generation of human Th1-like regulatory CD4+ T cells by an intrinsic IFN-γ- and T-bet-dependent pathway

Abstract

Murine Foxp3+ Treg have recently been shown to express T-bet, a transcription factor characteristic of Th1 effector cells. A human Treg phenotype equivalent has not been reported. Here, we show that naïve human CD4+ T cells incubated with low numbers of CD40-activated allogeneic B cells preferentially differentiate into alloantigen-specific CD4hiCD25hi Treg. These differentiated cells potently suppress effector T-cell responses and express T-bet, IFN-γ, and CXCR3, the features of Th1 effector cells. In contrast, co-culture of naïve CD4+ T cells with high numbers of allogeneic B cells results in CD4+CD25+ T cells that promote, rather than inhibit, effector T-cell responses, demonstrating the plasticity of CD4+ T-cell differentiation in response to alloantigen-presenting B cells. The optimal accumulation of CD4hiCD25hi Treg induced using higher T cell:B cell co-culture ratios was dependent on the expression of T-bet and endogenously produced IFN-γ. Induction of Treg-mediated suppression function in the Treg population was not. As CXCR3 confers the preferential trafficking of T cells to tissue sites of IFN-γ, these human Th1-like Treg might be useful for modulating pathological Th1 effector responses, such as that occurring during graft-versus-host disease or graft rejection. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.