title: Autoreactive Tbet-positive CD4 T cells develop independent of classic Th1 cytokine signaling during experimental autoimmune encephalomyelitis.
abstract: Many autoimmune chronic inflammatory diseases, including multiple sclerosis, are associated with the presence of Th1 and Th17 effector CD4 T cells. Paradoxically, the principal Th1 cytokine IFN-γ does not appear necessary for disease, but the key Th1-associated transcription factor Tbet has been reported to be essential for disease development. This conundrum propelled us to investigate the regulation of this transcription factor during autoimmunity. Following the onset of experimental autoimmune encephalomyelitis, we observed a preferential upregulation of Tbet by CD4 T cells within the CNS, but not the secondary lymphoid organs. These Tbet-positive CD4 T cells were capable of producing the cytokine IFN-γ, and a proportion of these cells produced both IFN-γ and IL-17A. Interestingly, these Tbet-positive cells were present in high frequencies during disease in IFN-γ-deficient mice. Moreover, we found that CD4 T cells from IFN-γ-deficient/IFN-γ reporter mice upregulated the Thy1.1 reporter, indicating the presence of Th1 or Th1-like, Tbet-positive CD4 T cells even in the absence of the cardinal Th1 cytokine IFN-γ. These IFN-γ-deficient Th1-like cells not only maintain multiple Th1 properties but also exhibit increased expression of genes associated with the Th17 phenotype. We further examined the requirement of other Th1-associated molecules in controlling Tbet expression during experimental autoimmune encephalomyelitis and noted that STAT1, IL-12, and IFN-γ were dispensable for the induction of Tbet in vivo. Hence, this study highlights the complex regulation of Tbet and the potential unrecognized role for Th1 cells during autoimmunity.
authors: Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Wen-I
authors: WI
authors: Yeh
authors: Ian L
authors: IL
authors: McWilliams
authors: Laurie E
authors: LE
authors: Harrington
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000276:immunology*; D016207:Cytokines / Q000502:physiology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000096:biosynthesis*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000098815:T-bet Transcription Factor
chemical_list: D016207:Cytokines; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor