B7 co-stimulation antagonizes RORγt+ regulatory T cells and tolerance to gut microbiota 2254003

Abstract Introduction Regulatory T (Treg) cells recognizing dietary or microbiota-derived antigens express RORγt and are essential for intestinal immune tolerance. A recent paradigm-shifting finding revealed that these cells require major histocompatibility complex class II (MHCII) on RORγt+ antigen-presenting cells (APCs) to provide signal one. Here, we evaluated signal two and found that broad blockade of co-stimulatory molecules B7-1 (CD80) and B7-2 (CD86) unexpectedly provoked the expansion of microbiota-specific RORγt+ Treg cells. Methods Cutting-edge transgenic, knockout, and adoptive-transfer mouse models were employed to define how the induction of RORγt+ Treg cells is regulated by MHCII (signal one) from RORγt+ APCs and B7 co-stimulation (signal two) from non-RORγt+ APCs to maintain immune tolerance to gut microbiota. Flow cytometry, ex vivo T cell differentiation, histology, and colitis models induced by Helicobacter hepaticus plus anti—IL-10R antibody, combined with co-stimulation blockade and CTLA4-Ig treatment, were integrated to dissect the interplay between RORγt+ APCs and RORγt+ Tregs. Results Mechanistically, B7/CD28-dependent Akt signaling antagonizes the core transcriptional program of RORγt+ Treg cells through the Forkhead box protein O1 (Foxo1) pathway. The expansion of RORγt+ Tregs was recapitulated by CTLA4-Ig but required MHCII (signal one) on RORγt+ APCs together with inhibition of B7 co-stimulation (signal two) from non-RORγt+ APCs. CTLA4-Ig treatment during pathobiont colonization and IL-10R blockade restored microbiota-specific RORγt+ Treg generation and protected against experimental colitis, reducing IL-17+ and TNF+ T cells. Conclusion These results mechanistically define that B7 co-stimulation limits microbiota-specific RORγt+ Treg cells, while identifying CTLA4-Ig as an approach to enhance immune tolerance and reduce inflammatory cytokines in the intestine when acting in concert with RORγt+ APCs, provoking a novel therapeutic strategy for patients with chronic intestinal inflammation. Funding Source NIH/NCI - K99CA290052 Topic Categories Mucosal and Regional Immunology (MUC)