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The mechanisms that regulate LV development are incompletely understood. Here, we show that the deletion of the GPCR sphingosine 1-phosphate receptor-1 (S1PR1) from lymphatic endothelial cells (LECs) results in fewer LVs. Interestingly, LVs that remained in the terminal ileum-draining lymphatic vessels were specifically dysfunctional. Furthermore, tertiary lymphoid organs (TLOs) formed in the terminal ileum of the mutant mice. TLOs in this location are associated with ileitis in humans and mice. However, mice lacking S1PR1 did not develop obvious characteristics of ileitis. Mechanistically, S1PR1 regulates shear stress signaling and the expression of the valve-regulatory molecules FOXC2 and connexin-37. Importantly, Foxc2+\/\u2212 mice, a model for lymphedema-distichiasis syndrome, also develop TLOs in the terminal ileum. Thus, we have discovered S1PR1 as a previously unknown regulator of LV and TLO development. We also suggest that TLOs are a sign of subclinical inflammation that can form due to lymphatic disorders in the absence of ileitis.<\/jats:p>","DOI":"10.1084\/jem.20241799","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T02:20:48Z","timestamp":1747794048000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["S1PR1 regulates lymphatic valve development and tertiary lymphoid organ formation in the ileum"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8743-7510","authenticated-orcid":true,"given":"Xin","family":"Geng","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035z6xf33","id-type":"ROR","asserted-by":"publisher"}],"name":"Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation 1 , Oklahoma City, 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