Abstract
The discovery of Th17 cell plasticity, in which CD4+ IL-17–producing Th17 cells give rise to IL-17/IFN-γ double-producing cells and Th1-like IFNγ+ ex-Th17 lymphocytes, has raised questions regarding which of these cell types contribute to immunopathology during inflammatory diseases. In this study, we show using Helicobacter hepaticus-induced intestinal inflammation that IL-17ACre– or Rag1Cre-mediated deletion of Tbx21 has no effect on the generation of IL-17/IFN-γ double-producing cells, but leads to a marked absence of Th1-like IFNγ+ ex-Th17 cells. Despite the lack of Th1-like ex-Th17 cells, the degree of H. hepaticus-triggered intestinal inflammation in mice in which Tbx21 was excised in IL-17–producing or Rag1-expressing cells is indistinguishable from that observed in control mice. In stark contrast, using experimental autoimmune encephalomyelitis, we show that IL-17ACre–mediated deletion of Tbx21 prevents the conversion of Th17 cells to IL-17A/IFN-γ double-producing cells as well as Th1-like IFN-γ+ ex-Th17 cells. However, IL-17ACre–mediated deletion of Tbx21 has only limited effects on disease course in this model and is not compensated by Ag-specific Th1 cells. IL-17ACre–mediated deletion of Rorc reveals that RORγt is essential for the maintenance of the Th17 cell lineage, but not immunopathology during experimental autoimmune encephalomyelitis. These results show that neither the single Th17 subset, nor its progeny, is solely responsible for immunopathology or autoimmunity.
Highlights
The immune system needs to rapidly and robustly respond to pathogenic threats, whereas inappropriate responses to benign stimuli must be avoided
To determine what cell population harbors Ag-specific T cells, we used MOG38–49 MHC-II tetramer staining in IL-17Acre Rosa26stop-tdRFP IFN-geYFP mice in which IL-17 is lineage marked by RFP and IFN-g protein expression reported via eYFP [20, 41]
The majority of CD4+ T cells encountered in the CNS in both IL-17ADTbet and IL-17AWT control mice were originally derived from the Th17 cell subset, as we reported before in IL-17AWT control mice [20], it was possible that Ag specificity could have risen in the bona fide Th1 cell population
Summary
The immune system needs to rapidly and robustly respond to pathogenic threats, whereas inappropriate responses to benign stimuli must be avoided. Regulatory T cells (Treg) were identified based on their ability to prevent autoimmunity [2] and were able to reduce the activity of both Th1 and Th2 subsets, thereby upholding the paradigm of two ultimate effector lineage fates. Ag-inexperienced CD4+ T cells can differentiate into multiple lineages, including Th1, Th2, Treg, Th17, Th9, and follicular Th cells (Tfh) [3]. Th subsets are largely defined by the signature cytokines they produce and their lineage-associated transcription factors. Th1 cells are characterized by their expression of the cytokine IFN-g and the transcription factor T box expressed in T cells (Tbet) [6]. Th1 cells were initially thought to be critical in autoimmune disorders such as rheumatoid arthritis, type 1 diabetes, and multiple sclerosis, the focus rapidly shifted to Th17 cells being involved in these diseases [10, 11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
