{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:58:49Z","timestamp":1790834329710,"version":"4.1.0"},"reference-count":32,"publisher":"American Society for Clinical Investigation","issue":"16","funder":[{"name":"NIH","award":["R01 AI132771"],"award-info":[{"award-number":["R01 AI132771"]}]},{"DOI":"10.13039\/100002570","name":"American Association of Immunologists","doi-asserted-by":"crossref","award":["Careers in Immunology Fellowship"],"award-info":[{"award-number":["Careers in Immunology Fellowship"]}],"id":[{"id":"10.13039\/100002570","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,8,22]]},"abstract":"<jats:p>\n                    T follicular regulatory (TFR) cells are found in the germinal center (GC) response and help shape the antibody (Ab) response. However, the precise role of TFR cells in the GC is controversial. Here, we addressed TFR cell function using mice with impaired TFR cell development (\n                    <jats:italic>Bcl6-flox\/Foxp3-cre<\/jats:italic>\n                    , or Bcl6FC mice), mice with augmented TFR cell development (\n                    <jats:italic>Blimp1-flox\/Foxp3-cre<\/jats:italic>\n                    , or Blimp1FC mice), and two different methods of immunization. Unexpectedly, GC B cell levels positively correlated with TFR cell levels. Using a gene profiling approach, we found that TFH cells from TFR-deficient mice showed strong upregulation of granzyme B (\n                    <jats:italic>Gzmb<\/jats:italic>\n                    ) and other effector CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell genes, many of which were Stat4 dependent. The upregulation of cytotoxic genes was the highest in TFH cells from TFR-deficient mice where Blimp1 was also deleted in Foxp3\n                    <jats:sup>+<\/jats:sup>\n                    regulatory T cells (\n                    <jats:italic>Bcl6-flox\/Prdm1-flox\/Foxp3-cre<\/jats:italic>\n                    [DKO] mice). Granzyme B\u2013 and Eomesodermin-expressing TFH cells correlated with a higher rate of apoptotic GC B cells. Klrg1\n                    <jats:sup>+<\/jats:sup>\n                    TFH cells from DKO mice expressed higher levels of\n                    <jats:italic>Gzmb<\/jats:italic>\n                    . Our data show that TFR cells repress the development of abnormal cytotoxic TFH cells, and the presence of cytotoxic TFH cells correlates with a lower GC and Ab response. Our data show what we believe is a novel mechanism of action for TFR cells helping the GC response.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.128076","type":"journal-article","created":{"date-parts":[[2019,8,21]],"date-time":"2019-08-21T11:01:11Z","timestamp":1566385271000},"source":"Crossref","is-referenced-by-count":63,"title":["Follicular regulatory T cells inhibit the development of granzyme B\u2013expressing follicular helper T cells"],"prefix":"10.1172","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1350-7364","authenticated-orcid":true,"given":"Markus M.","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8645-5377","authenticated-orcid":true,"given":"Shuyi","family":"Fang","sequence":"additional","affiliation":[{"name":"Indiana University School of Informatics and Computing, Indiana University\u2013Purdue University Indianapolis, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9286-6562","authenticated-orcid":true,"given":"Jun","family":"Wan","sequence":"additional","affiliation":[{"name":"Indiana University School of Informatics and Computing, Indiana University\u2013Purdue University Indianapolis, Indianapolis, Indiana, USA."},{"name":"Department of Medical and Molecular Genetics and"},{"name":"Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7226-8936","authenticated-orcid":true,"given":"Alexander L.","family":"Dent","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2019,8,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-020711-075032"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.03.003"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-031210-101400"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2425"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2426"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1101328"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201546094"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12411"},{"key":"B9","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.01536","article-title":"Unexpected help: follicular regulatory T cells in the germinal center","volume":"9","author":"Xie","year":"2018","journal-title":"Front 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