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Despite their circulating nature, NK cells can establish residency in selected tissues during ontogeny, forming a distinct functional subset. The mechanisms that initiate, maintain, and regulate the conversion of NK cells into tissue-resident NK (trNK) cells are currently not well understood. Here, we identify autocrine transforming growth factor-\u03b2 (TGF-\u03b2) as a cell-autonomous driver for NK cell tissue residency across multiple glandular tissues during development. Cell-intrinsic production of TGF-\u03b2 was continuously required for the maintenance of trNK cells and synergized with Hobit to enhance cytotoxic function. Whereas autocrine TGF-\u03b2 was redundant in tumors, our study revealed that NK cell\u2013derived TGF-\u03b2 allowed the expansion of cytotoxic trNK cells during local infection with murine cytomegalovirus (MCMV) and contributed to viral control in the salivary gland. Collectively, our findings reveal tissue-specific regulation of trNK cell differentiation and function by autocrine TGF-\u03b21, which is relevant for antiviral immunity.<\/jats:p>","DOI":"10.1084\/jem.20240930","type":"journal-article","created":{"date-parts":[[2024,11,21]],"date-time":"2024-11-21T02:20:49Z","timestamp":1732155649000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":37,"title":["Autocrine TGF-\u03b21 drives tissue-specific differentiation and function of resident NK cells"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0776-6896","authenticated-orcid":true,"given":"Colin","family":"Sparano","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02crff812","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Experimental Immunology, University of Z\u00fcrich 1 , 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