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A recent paradigm shift found these cells require major histocompatibility complex class II (MHCII) on ROR\u03b3t+ antigen-presenting cells (APCs) rather than conventional dendritic cells (cDCs) for signal one. Here, we evaluate signal two and unexpectedly find that costimulatory molecules B7-1 (CD80) and B7-2 (CD86) antagonize the generation of microbiota-specific ROR\u03b3t+ Treg cells. Gain-of-function or loss-of-function therapeutics targeting B7 via CTLA-4 exert reciprocal effects on the generation of microbiota-specific ROR\u03b3t+ Treg cells. This axis was independent of B7 on ROR\u03b3t+ APCs but required MHCII on this cell type. Finally, CTLA4-Ig treatment restores microbiota-specific ROR\u03b3t+ Treg cell generation and protects from experimental intestinal inflammation induced by pathobiont colonization with IL-10R signaling blockade. These results define that ROR\u03b3t+ Treg cells are uniquely restrained by B7 costimulation, while CTLA4-Ig enhances immune tolerance in the intestine when acting cooperatively with ROR\u03b3t+ APCs.<\/jats:p>","DOI":"10.1084\/jem.20251094","type":"journal-article","created":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T06:21:07Z","timestamp":1774074067000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["B7 costimulation antagonizes ROR\u03b3t+ regulatory T cells and immune tolerance in the intestine"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8509-7969","authenticated-orcid":true,"given":"Mengze","family":"Lyu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02r109517","id-type":"ROR","asserted-by":"publisher"}],"name":"Weill Cornell Medicine, Cornell University 1 Joan and Sanford I. 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