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Upon recognition, they become activated, produce proinflammatory cytokines, chemokines, and cytotoxic molecules. MAIT cells are also activated by cytokines independently of T cell receptor (TCR) engagement; however, these two signals can also act in concert to fine\u2010tune MAIT cell functions. Additionally, multiple other co\u2010stimulatory signals have also been reported that can boost MAIT cell effector responses to TCR or cytokine stimulation. However, a comprehensive study exploring the role of surface\u2010bound TNF receptor superfamily (TNFRSF) molecule 4\u20101BB, well known for its co\u2010stimulatory function during conventional T cell activation, is lacking in the context of MAIT cells. In this study, we show that 4\u20101BB is the earliest and most highly expressed TNFRSF co\u2010stimulatory molecule on MAIT cells upon activation by\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Escherichia coli<\/jats:italic>\n                    <\/jats:styled-content>\n                    , with expression seen as early as 6\u2009h where it was predominantly MR1 mediated. 4\u20101BB expression on MAIT cells following late activation was due to both TCR signaling and cytokine signaling. We found marked differences in MAIT cell activation and cytokine expression between 4\u20101BB+ and 4\u20101BB\u2010 MAIT cells suggesting 4\u20101BB expression on MAIT cells is associated with functional superiority. By blocking 4\u20101BB signaling or coculturing with a 4\u20101BBL overexpressing cell line, we demonstrated an important role of co\u2010stimulation via 4\u20101BB in MAIT cells during activation. Expression and signaling via 4\u20101BB also enhanced T\u2010bet and Blimp1 expression. In summary, our study confirms a role for 4\u20101BB signaling during MAIT cell activation.\n                  <\/jats:p>","DOI":"10.1111\/imcb.70142","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T08:09:52Z","timestamp":1782202192000},"page":"686-699","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["4\u20101BB Expression and Signaling Regulates MAIT Cell Activation and Effector Functions"],"prefix":"10.1111","volume":"104","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7475-1075","authenticated-orcid":false,"given":"Lamichhane","family":"R","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology University of Otago  Dunedin New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Williams","family":"J","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology University of Otago  Dunedin New 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