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In the small intestine, T\n                    <jats:sub>RM<\/jats:sub>\n                    cells are found in at least two distinct subpopulations: one with higher expression of effector molecules and another with greater memory potential\n                    <jats:sup>1<\/jats:sup>\n                    . However, the origins of this diversity remain unknown. Here we proposed that distinct tissue niches drive the\u00a0phenotypic heterogeneity\u00a0of T\n                    <jats:sub>RM<\/jats:sub>\n                    cells. To test this, we leveraged spatial transcriptomics of human samples, a mouse model of acute systemic viral infection and a newly established strategy for pooled optically encoded gene perturbations to profile the locations, interactions and transcriptomes of pathogen-specific T\n                    <jats:sub>RM<\/jats:sub>\n                    cell differentiation at single-transcript resolution. We developed computational approaches to capture cellular locations along three anatomical axes of the small intestine and to visualize the spatiotemporal distribution of cell types and gene expression. Our study reveals that the regionalized signalling of the intestinal architecture supports two distinct T\n                    <jats:sub>RM<\/jats:sub>\n                    cell states: differentiated T\n                    <jats:sub>RM<\/jats:sub>\n                    cells and progenitor-like T\n                    <jats:sub>RM<\/jats:sub>\n                    cells, located in the upper villus and lower villus, respectively. This diversity is mediated by distinct ligand\u2013receptor activities, cytokine gradients and specialized cellular contacts. Blocking TGF\u03b2 or CXCL9 and CXCL10 sensing by antigen-specific CD8 T cells revealed a model consistent with anatomically\u00a0delineated, early fate specification. Ultimately, our framework for the study of tissue immune networks reveals that T cell location and functional state are fundamentally intertwined.\n                  <\/jats:p>","DOI":"10.1038\/s41586-024-08466-x","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T11:06:37Z","timestamp":1737543997000},"page":"483-492","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":109,"title":["Tissue-resident memory CD8 T cell diversity is spatiotemporally imprinted"],"prefix":"10.1038","volume":"639","author":[{"given":"Miguel","family":"Reina-Campos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5399-2205","authenticated-orcid":false,"given":"Alexander","family":"Monell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2884-083X","authenticated-orcid":false,"given":"Amir","family":"Ferry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6300-8128","authenticated-orcid":false,"given":"Vida","family":"Luna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kitty P.","family":"Cheung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6613-2354","authenticated-orcid":false,"given":"Giovanni","family":"Galletti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole E.","family":"Scharping","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kennidy K.","family":"Takehara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3860-3491","authenticated-orcid":false,"given":"Sara","family":"Quon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8634-031X","authenticated-orcid":false,"given":"Peter P.","family":"Challita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigid","family":"Boland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5997-9109","authenticated-orcid":false,"given":"Yun Hsuan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William H.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia S.","family":"Indralingam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5011-5989","authenticated-orcid":false,"given":"Hayley","family":"Neadeau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzie","family":"Alarc\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0799-6037","authenticated-orcid":false,"given":"Gene W.","family":"Yeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0873-6218","authenticated-orcid":false,"given":"John T.","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9594-1377","authenticated-orcid":false,"given":"Maximilian","family":"Heeg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5900-508X","authenticated-orcid":false,"given":"Ananda W.","family":"Goldrath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,22]]},"reference":[{"key":"8466_CR1","doi-asserted-by":"publisher","first-page":"808\u2013824","DOI":"10.1016\/j.immuni.2020.04.007","volume":"52","author":"JJ Milner","year":"2020","unstructured":"Milner, J. 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