Regulatory T cells (T reg cells) play a critical role in suppressing anti-tumor immunity, often resulting in unfavorable clinical outcomes across numerous cancers. However, systemic T reg depletion, while augmenting anti-tumor responses, also triggers detrimental autoimmune disorders. Thus, dissecting the mechanisms by which T reg cells navigate and exert their functions within the tumor microenvironment (TME) is pivotal for devising innovative T reg -centric cancer therapies. Our study highlights the role of peroxisome proliferator-activated receptor β/δ (PPARδ), a nuclear hormone receptor involved in fatty acid metabolism. Remarkably, PPARδ ablation in T reg escalated tumor growth and augmented the immunosuppressive characteristics of the TME. This absence of PPARδ spurred an increased expression of genes central to antigen presentation, notably CIITA and MHC II. Our results showcase a novel association where the absence of CIITA in PPARδ-deficient T reg bolsters anti-tumor responses, casting CIITA as a pivotal downstream regulator of PPARδ within T reg . In vitro assays demonstrated that elevated CIITA levels enhance the suppressive capacity of T reg , facilitated by an antigen-independent interaction between T reg -MHC II and T conv -TCR/CD4/Lag3. A significant revelation was the role of type 1 interferon as a TME signal that promotes the genesis of MHC II + T reg ; PPARδ deficiency intensifies this phenomenon by amplifying type 1 interferon signaling, mediated by a notable upsurge in JAK3 transcription and an increase of pSTAT1-Y701. In conclusion, the co-regulation between TME cues and PPARδ signaling shapes the adaptive and suppressive roles of T reg cells through the CIITA-MHC II pathway. Strategically targeting the potent MHC II + T reg population could open a new avenue for cancer therapies by boosting anti-tumor defenses while curbing autoimmune threats.
Highlights: PPARδ T reg conditional knockout mice show accelerated tumor growth due to increased expression of CIITA-MHC II. Type I interferon signal regulates T reg CIITA-MHC II axis in vitro and in vivo . PPARδ attenuates Type I interferon response and restrains CIITA-MHC II expression in T reg cells. T reg suppressive function is enhanced by T reg MHC II's direct interaction with TCR/CD4/Lag3 on T eff cells.