Stability and function of regulatory T cells expressing the transcription factor T-bet

Abstract

Adaptive immune responses are tailored to different types of pathogens through differentiation of naïve CD4 T cells into functionally distinct subsets of effector T cells (TH1, TH2, and TH17) defined by expression of key transcription factors (TFs)1. Regulatory T (Treg) cells comprise a distinct anti-inflammatory lineage specified by the X-linked TF Foxp32, 3. Paradoxically, some activated Treg cells express the aforementioned effector CD4 T cell TFs, which have been suggested to endow Treg cells with enhanced suppressive capacity4, 5, 6. Whether expression of these factors in Treg cells—akin to effector T cells—is indicative of heterogeneity of functionally discrete and stable differentiation states, or conversely may be readily reversible, is unknown. Here, we demonstrate that in Treg cells expression of the TH1-associated TF T-bet, induced at steady state and following infection, gradually becomes highly stable even under non-permissive conditions. Loss-of-function or elimination of T-bet-expressing Treg cells—but not of T-bet in Treg cells—resulted in severe TH1 autoimmunity. Conversely, following depletion of T-bet-negative Treg cells, remaining T-bet+ cells specifically inhibited TH1 and CD8 T cell activation in agreement with their co-localization with T-bet+ effector T cells. These results suggest an essential immunosuppressive function for T-bet+ Treg cells and indicate that Treg cell functional heterogeneity is a critical feature of immune tolerance.

Generation of RORγt+ Antigen-Specific T Regulatory 17 Cells from Foxp3+ Precursors in Autoimmunity

“…According to a recent study, it is possible that depletion of RORγt + Treg cells is needed to examine their function rather than deletion of RORγt expression in Treg cells (Levine et al, 2017). However, availability of an experimental system for selective depletion of RORγt + Treg cells in vivo is limited at the moment.…”

“…Considering that total ICOS hi Treg cell frequency were not changed after immunization even in the absence of RORγt (Figure 4A), ICOS hi CCR6 − Treg cells might have compensated for the absence of ICOS hi RORγt + CCR6 + Treg cells in RORγ f/f Foxp3 Cre mice. A recent study demonstrated that depletion of T-bet + Treg cells rather than deletion of Tbx21 gene in Treg cells resulted in Th1-dependent immunopathology (Levine et al, 2017). In this regard, selective depletion of RORγt + CCR6 + Treg cells after their development is required to address the functional relevance of the population in EAE as previously suggested (Kim et al, 2007).…”

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

“…This is supported by the detection of lineage‐specific transcription factors (e.g. Tbet,20 IRF421) being co‐expressed with FOXP3 in Treg subsets, using various mouse models, but this has yet to be confirmed in humans. It is possible that the balance of Treg to effector lineages may be altered under specific circumstances or that the Treg themselves may switch fates.…”

High self-reactivity drives T-bet and potentiates Treg function in tissue-specific autoimmunity

“…In line with the idea that TCR signaling strength is driving the transcriptional difference between CD5 hi and CD5 lo islet Tregs, CD5 hi Tregs from the islets showed a significant increase in expression of genes associated with TCR signaling (Zap70), as well as genes regulated by Nur77 directly downstream of TCR activation (Helios, Tnfrsf9, Itgae, Cst7) (30) ( Figure 3D). Moreover, many of the genes associated with Treg-suppressive function that were upregulated in CD5 hi islet Tregs were previously shown to be under the control of TCR (Ctla4, Icos, Lag3, Il10, Tigit) ( Figure 3E) (17,31). Interestingly, CD5…”

“…Overall, this suggests that high TCR self-reactivity drives Treg functional potential in the islets. Recent studies have shown that Tregs expressing T-bet and CXCR3 are indispensable for the control of Th1 immune responses, including autoimmune diabetes (31,32). Interestingly, CD5…”