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Here, we show that in robust CD4+ T cell responses, all early CXCR5+CD4+ T cells expressed CD25, and STAT5, which inhibits Tfh cell differentiation, was crucial for both non-Tfh and Tfh responses. We found that after T cell activation, the transient increase in BACH2 protein levels temporarily suppressed STAT5-mediated Blimp1 induction, licensing early CXCR5+CD25+CD4+ T cells to proliferate to STAT5 signaling without being suppressed for the subsequent Tfh cell differentiation. Furthermore, depending on the immunization route, location, and antigen dose, BACH2 exerted bidirectional regulation on the differentiation of CXCR5\u2212 versus CXCR5+ CD4+ T cells throughout the body. Our findings suggest BACH2 orchestrates systemic immunity, offering insights for harnessing CD4+ T cell responses in vaccines and treatments.<\/jats:p>","DOI":"10.1084\/jem.20251959","type":"journal-article","created":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T06:21:04Z","timestamp":1778912464000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Bidirectional regulation by BACH2 coordinates systemic CXCR5\u2212 vs. CXCR5+ CD4+ T cell differentiation"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9037-7463","authenticated-orcid":true,"given":"Andrew R.","family":"Schroeder","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/008s83205","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medicine, University of Alabama at Birmingham 1 Department of Microbiology, , Birmingham, AL,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7805-6969","authenticated-orcid":true,"given":"Fangming","family":"Zhu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/008s83205","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medicine, University of Alabama at Birmingham 1 Department of Microbiology, , Birmingham, AL,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9363-9816","authenticated-orcid":true,"given":"Xianyou","family":"Xia","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/008s83205","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medicine, University of Alabama at Birmingham 1 Department of Microbiology, , Birmingham, AL,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2915-7189","authenticated-orcid":true,"given":"Hui","family":"Hu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/008s83205","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medicine, University of Alabama at Birmingham 1 Department of Microbiology, , Birmingham, AL,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"2026060809395710300_bib1","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1038\/ni.3753","article-title":"BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency","volume":"18","author":"Afzali","year":"2017","journal-title":"Nat. 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