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We found that intestinal \u03b2-defensin expression was inadequately induced in response to inflammation in two independent cohorts of patients with aGVHD and in a murine aGVHD model. Treatment of mice with hBD-2 reduced GVHD severity and mortality and modulated the intestinal microbiota composition, resulting in reduced neutrophil infiltration in the ileum. Furthermore, hBD-2 treatment decreased proliferation and proinflammatory cytokine production by allogeneic T cells in vivo while preserving the beneficial graft-versus-leukemia effect. Using transcriptome and kinome profiling, we found that hBD-2 directly dampened primary murine and human allogeneic T cell proliferation, activation, and metabolism in a CCR2- and CCR6-independent manner by reducing proximal T cell receptor signaling. Furthermore, hBD-2 treatment diminished alloreactive T cell infiltration and the expression of genes involved in T cell receptor signaling in the ilea of mice with aGVHD. Together, we found that both human and murine aGVHD were characterized by a lack of intestinal \u03b2-defensin induction and that recombinant hBD-2 represents a potential therapeutic strategy to counterbalance endogenous hBD-2 deficiency.<\/jats:p>","DOI":"10.1126\/scitranslmed.abp9675","type":"journal-article","created":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T18:58:21Z","timestamp":1671649101000},"source":"Crossref","is-referenced-by-count":25,"title":["Human \u03b2-defensin 2 ameliorates acute GVHD by limiting ileal neutrophil infiltration and restraining T cell receptor signaling"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0723-8110","authenticated-orcid":true,"given":"Tamina","family":"R\u00fcckert","sequence":"first","affiliation":[{"name":"Department of Medicine I, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, 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