T-bet inhibits the in vivo differentiation of parasite-specific CD4+ Th17 cells in a T cell-intrinsic manner.
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-gamma. However, a robust Th17 response developed concomitant with Th1 responses. Despite significant IFN-gamma 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-gamma 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.
Department of Microbiology and Immunology, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 23298, USA.
Siqi
S
Guo
Dustin
D
Cobb
Ronald B
RB
Smeltz
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D014355:Chagas Disease / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D014349:Trypanosoma cruzi; D000098815:T-bet Transcription Factor
D020381:Interleukin-17; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma