title: 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 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.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong SAR, P R China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zheng
authors.forename: Yinping
authors.initials: Y
authors.lastname: Liu
authors.forename: Gang
authors.initials: G
authors.lastname: Qin
authors.forename: Kwok-Tai
authors.initials: KT
authors.lastname: Lam
authors.forename: Jing
authors.initials: J
authors.lastname: Guan
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xiang
authors.forename: David B
authors.initials: DB
authors.lastname: Lewis
authors.forename: Yu-Lung
authors.initials: YL
authors.lastname: Lau
authors.forename: Wenwei
authors.initials: W
authors.lastname: Tu
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D054367:Receptors, CXCR3 / Q000276:immunology; D020825:T-Box Domain Proteins / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D019013:CD40 Antigens; C515187:CXCR3 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D054367:Receptors, CXCR3; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma