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Initial diversification is influenced by signals sensed during T cell priming within lymphoid tissues. However, the rules governing how cellular heterogeneity is spatially encoded in vivo remain unclear. Here, we show that immunization establishes concentration gradients of antigens and inflammation across interconnected chains of draining lymph nodes (IC-LNs). While T cells are activated at all sites, individual IC-LNs elicit divergent responses: proximal IC-LNs favor the generation of effector cells, whereas distal IC-LNs promote formation of central memory precursor cells. Although both proximal and distal sites contribute to anamnestic responses, T cells from proximal IC-LNs preferentially provide early effector responses at inflamed tissues. Conversely, T cells from distal IC-LNs demonstrate an enhanced capacity to generate long-lasting responses to chronic antigens in cancer settings, including after checkpoint blockade therapy. Therefore, formation of spatial gradients across lymphatic chains following vaccination regulates the magnitude, heterogeneity, and longevity of T cell responses.<\/jats:p>","DOI":"10.1084\/jem.20241311","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T01:57:26Z","timestamp":1746064646000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Lymphatic chain gradients regulate the magnitude and heterogeneity of T cell responses to vaccination"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0221-3566","authenticated-orcid":true,"given":"Michael T.","family":"Conlon","sequence":"first","affiliation":[{"name":"University of Washington School of Medicine 1 Department of Immunology, , Seattle, WA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8674-5924","authenticated-orcid":true,"given":"Jessica Y.","family":"Huang","sequence":"additional","affiliation":[{"name":"University of Washington School of Medicine 1 Department of Immunology, , Seattle, WA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5406-8308","authenticated-orcid":true,"given":"Michael Y.","family":"Gerner","sequence":"additional","affiliation":[{"name":"University of Washington School of Medicine 1 Department of Immunology, , Seattle, WA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"2025043021572259100_bib1","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.immuni.2023.12.006","article-title":"Reversible, tunable epigenetic silencing of TCF1 generates flexibility in the T cell memory decision","volume":"57","author":"Abadie","year":"2024","journal-title":"Immunity"},{"key":"2025043021572259100_bib2","doi-asserted-by":"publisher","first-page":"8161","DOI":"10.1128\/JVI.00889-12","article-title":"Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection","volume":"86","author":"Angelosanto","year":"2012","journal-title":"J. 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