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T-bet Inhibits the In Vivo Differentiation of Parasite-Specific CD4⁺ Th17 Cells in a T Cell-Intrinsic Manner¹

Department of Microbiology and Immunology, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 23298

CD4⁺ Th17 cells have emerged as a new T cell subset in the Th1/Th2 paradigm, and efforts have shifted toward understanding the factors that regulate their development in vivo. To analyze the role of the transcription factor T-bet in regulation of Th17 cells, we used a murine model of Trypanosoma cruzi infection, a protozoan parasite that causes Chagas disease in humans. Infection of Tbx21^–/– mice led to normal, unimpaired development of Ag-specific CD4⁺ T cells producing IFN-. However, a robust Th17 response developed concomitant with Th1 responses. Despite significant IFN- production, the physiological effects of Th17 responses prevailed as there was a sharp increase in Gr-1⁺Ly6G⁺ neutrophils. Adoptive transfer of T cells from infected Tbx21^–/– mice into Rag-2^–/– mice (Tbx21^+/+) revealed that CD4⁺ T cells maintained their IL-17-producing phenotype, including those cells capable of producing both IFN- and IL-17. Furthermore, and in contrast to the effects of IL-2 on Th17 development, IL-2 had no effect on IL-17 production by primed T cells. Importantly, adoptive transfer of T cells from naive Tbx21^–/– mice into infected Rag-2^–/– mice recapitulated the differentiation of T. cruzi-specific Th17 cells observed in infected Tbx21^–/– mice. Conversely, transfer of wild-type T cells into infected Tbx21^–/– mice did not reveal an increase in Th17 development. These results demonstrate that T-bet regulates the differentiation of T. cruzi-specific Th17 cells in vivo in a T cell-intrinsic manner. These data provide important insight into the role of T-bet in regulation of parasite-specific Th17 responses.

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¹ This work was supported by funds provided by Virginia Commonwealth University and the Department of Microbiology and Immunology, as well as a grant from the Thomas F. and Kate Miller Jeffress Memorial Trust.

² Address correspondence and reprint requests to Dr. Ronald Smeltz, Virginia Commonwealth University, 1217 East Marshall Street, Medical Sciences Building Room 325, Richmond, VA 23298. E-mail address: rbsmeltz{at}vcu.edu

³ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; ICS, intracellular cytokine staining; p.i., postinfection.