Singular role for T-BET ⁺ CXCR3 ⁺ regulatory T cells in protection from autoimmune diabetes

Abstract

Foxp3+ regulatory T (Treg) cells are crucial for restraining inflammation in a variety of autoimmune diseases, including type 1 diabetes (T1D). However, the transcriptional and functional phenotypes of Treg cells within the pancreatic lesion remain poorly understood. Here we characterized pancreas-infiltrating Treg cells in the NOD mouse model of T1D and uncovered a substantial enrichment of the Treg subpopulation expressing the chemokine receptor CXCR3. Accumulation of CXCR3 + Treg cells within pancreatic islets was dependent on the transcription factor T-BET, and genetic ablation of T-BET increased the onset and penetrance of disease, abrogating the sex bias normally seen in the NOD model. Both male and female mice lacking T-BET + Treg cells showed a more aggressive insulitic infiltrate, reflected most prominently by elevated production of type 1 cytokines. Our results suggest the possibility of fine therapeutic targeting of Treg cells, in a tissue-and cell-subset-specific fashion, as a more focused immunotherapy for T1D.immunoregulation | immunogenomics | Treg subsets

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

“…Several groups have described cotranscription factor expression by Tregs as being necessary for their ability to suppress specific T helper lineages (32,(44)(45)(46)(47). Explicitly, coexpression of Foxp3 and T-bet by Tregs is indispensable for their ability to prevent autoimmune diabetes (32). In line with this idea, RNA-seq analysis revealed that functionally superior CD5 hi islet Tregs exhibited an enhanced T-bet program ( Figure 3F).…”

“…ICOS has previously been shown to identify a highly functional islet-infiltrating Treg population, which preferentially upregulates CXCR3, suggesting an important role for TCR in driving the program necessary for regulation of Th1 islet autoimmunity (32,52,53).…”

“…It was recently demonstrated that Treg-specific deletion of T-bet abrogated the ability of Tregs to prevent autoimmune diabetes in NOD mice (32). On the other hand, under some circumstances, T-bet -and subsequently IFNγ -expression can lead to Treg instability (48,(64)(65)(66).…”

“…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…”

“…Local inflammatory cues direct Tregs to take on distinct phenotypic changes and upregulate T helper lineage transcription factors that mirror that of their target effector subset (44-46). Several groups have described cotranscription factor expression by Tregs as being necessary for their ability to suppress specific T helper lineages (32,(44)(45)(46)(47). Explicitly, coexpression of Foxp3 and T-bet by Tregs is indispensable for their ability to prevent autoimmune diabetes (32).…”