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Here, we show that TMEM16F is required to curb excessive T cell responses in chronic infection with virus. TMEM16F-deficient T cells are hyperactivated during the early phase of infection, exhibiting increased proliferation and cytokine production. Interestingly, this overactivation ultimately leads to severe T cell exhaustion and the inability of the host to control viral burden. Mechanistically, we identify TMEM16F as the dominant lipid scramblase in T lymphocytes that transports phospholipids across membranes. TMEM16F is located in late endosomes, where it facilitates the generation of multivesicular bodies for TCR degradation and signal termination. Consequently, TMEM16F deficiency results in sustained signaling and augmented T cell activation. Our results demonstrate that scramblase restricts TCR responses to avoid overactivation, ensuring a well-balanced immune response in chronic infectious disease.<\/jats:p>","DOI":"10.1084\/jem.20160612","type":"journal-article","created":{"date-parts":[[2016,10,24]],"date-time":"2016-10-24T10:12:33Z","timestamp":1477303953000},"page":"2759-2772","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":47,"title":["Scramblase TMEM16F terminates T cell receptor signaling to restrict T cell exhaustion"],"prefix":"10.1084","volume":"213","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9511-9383","authenticated-orcid":false,"given":"Yu","family":"Hu","sequence":"first","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Hyung","family":"Kim","sequence":"additional","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangmin","family":"He","sequence":"additional","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Department of Cell Biology, Harvard Medical School, Boston, MA 02115 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wan","sequence":"additional","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Kim","sequence":"additional","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0590-8320","authenticated-orcid":false,"given":"Melanie","family":"Flach","sequence":"additional","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0559-893X","authenticated-orcid":false,"given":"Tom","family":"Kirchhausen","sequence":"additional","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Department of Cell Biology, Harvard Medical School, Boston, MA 02115 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Vortkamp","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, University Duisburg-Essen, 45117 Essen, Germany 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Winau","sequence":"additional","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2016,10,24]]},"reference":[{"key":"2023072608593396800_bib1","doi-asserted-by":"publisher","first-page":"5164","DOI":"10.1111\/febs.12427","article-title":"Do signalling endosomes play a role in T cell activation?","volume":"280","author":"Benzing","year":"2013","journal-title":"FEBS J."},{"key":"2023072608593396800_bib2","doi-asserted-by":"publisher","first-page":"2724","DOI":"10.1016\/j.febslet.2010.03.020","article-title":"Phospholipid scramblase: an update","volume":"584","author":"Bevers","year":"2010","journal-title":"FEBS Lett."},{"key":"2023072608593396800_bib3","doi-asserted-by":"publisher","first-page":"15016","DOI":"10.1073\/pnas.0801497105","article-title":"Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade","volume":"105","author":"Blackburn","year":"2008","journal-title":"Proc. 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