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

Eur J Immunol. 2011 Jan;41(1):128-39. doi: 10.1002/eji.201040724. Epub 2010 Dec 1.


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 CD4(hi) CD25(hi) 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 CD4(hi) CD25(hi) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD40 Antigens / immunology
  • Cells, Cultured
  • Coculture Techniques
  • Forkhead Transcription Factors / immunology
  • Humans
  • Interferon-gamma / immunology*
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Lymphocyte Activation / immunology
  • Receptors, CXCR3 / immunology
  • T-Box Domain Proteins / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • Th1 Cells / immunology*


  • CD40 Antigens
  • CXCR3 protein, human
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • IL2RA protein, human
  • Interleukin-2 Receptor alpha Subunit
  • Receptors, CXCR3
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Interferon-gamma