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Here, we report two siblings homozygous for a novel LCK variant (c.1318C&amp;gt;T; P440S) characterized by T cell lymphopenia with skewed memory phenotype, infant-onset recurrent infections, failure to thrive, and protracted diarrhea. The patients\u2019 T cells show residual TCR signal transduction and proliferation following anti-CD3\/CD28 and phytohemagglutinin (PHA) stimulation. We demonstrate in mouse models that complete (Lck\u2212\/\u2212) versus partial (LckP440S\/P440S) loss-of-function LCK causes disease with differing phenotypes. While both Lck\u2212\/\u2212 and LckP440S\/P440S mice exhibit arrested thymic T cell development and profound T cell lymphopenia, only LckP440S\/P440S mice show residual T cell proliferation, cytokine production, and intestinal inflammation. Furthermore, the intestinal disease in the LckP440S\/P440S mice is prevented by CD4+ T cell depletion or regulatory T cell transfer. These findings demonstrate that P440S LCK spares sufficient T cell function to allow the maturation of some conventional T cells but not regulatory T cells\u2014leading to intestinal inflammation.<\/jats:p>","DOI":"10.1084\/jem.20230927","type":"journal-article","created":{"date-parts":[[2023,10,28]],"date-time":"2023-10-28T02:21:10Z","timestamp":1698459670000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation"],"prefix":"10.1084","volume":"221","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1553-1499","authenticated-orcid":true,"given":"Victor G.","family":"Lui","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03wmf1y16","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Medicine, University of Colorado Anschutz Medical Campus 1 Department of Immunology and Microbiology, , Aurora, CO, 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