Abstract Background T cells critically shape intestinal inflammation in IBD. However, increasing evidence supports a critical role also of the B cell compartment, as suggested by the identification of anti-αvβ6 auto-antibodies 1, and by successful treatment of ulcerative colitis with CD19 CAR-T cells 2. Consistently, the switch from an IgA-secreting to an IgG-secreting environment is associated with more pro-inflammatory signaling and tissue damage in IBD 3. Thus, the homing process of antibody-secreting cells (ASC) from the circulation into the large intestine might also constitute an interesting therapeutic target to reverse infiltration of auto-reactive or IgG-secreting B lineage cells and to alter the humoral host-microbiota interaction. So far, gut-specific trafficking programmes for ASC remain poorly defined 4. Here, we studied the colon-homing receptor GPR15 as a candidate for ASC recruitment to the large intestine. Methods Circulating plasmablasts (PB) and early plasma cells (PC) from patients with IBD and healthy controls were studied for the expression of GPR15, gut-homing integrins and immunoglobulin isotypes by flow cytometry. The functional relevance of the GPR15:GPR15L axis was assessed in MAdCAM-1–dependent transwell transmigration assays with human PB/PC stimulated with GPR15L or CCL28. Bulk RNA-sequencing data from the TRR241/IBDome cohort and published colonic single-cell RNA-sequencing datasets were analysed for associations between GPR15, disease activity and IgA/IgG heavy chain expression. Results GPR15 was highly co-expressed with gut-homing integrins α4β7 and α4β1 on circulating human PB/PC, and IgA+ cells showed markedly higher GPR15 expression than IgA− cells (Figure 1). GPR15L strongly enhanced transmigration of human PB/PC across MAdCAM-1 in vitro, whereas CCL28 had only minor effects, indicating a specific role for GPR15L signaling in integrin-dependent gut homing. In colonic bulk RNA-seq, higher mucosal GPR15 expression correlated inversely with clinical and histologic disease activity in ulcerative colitis and was positively associated with IgA, but not IgG, heavy chain transcripts. Single-cell RNA-seq of human colonic plasma cells confirmed enrichment of GPR15 and integrin β7 in IgA-expressing clusters. Conclusion Our data support the hypothesis that GPR15:GPR15L preferentially affects the intestinal trafficking process of ASC and thereby mediates intestinal inflammation in IBD. References: 1 Kuwada T, Shiokawa M, Kodama Y, et al. Identification of an Anti-Integrin αvβ6 Autoantibody in Patients With Ulcerative Colitis. Gastroenterology. 2021;160(7):2383-2394.e21. doi:10.1053/j.gastro.2021.02.019 2 Müller F, Atreya R, Völkl S, et al. CD19 CAR T-Cell Therapy in Multidrug-Resistant Ulcerative Colitis. N Engl J Med. 2025;393(12):1239-1241. doi:10.1056/NEJMc2508023 3 Uzzan M, Martin JC, Mesin L, et al. Ulcerative colitis is characterized by a plasmablast-skewed humoral response associated with disease activity. Nat Med. 2022;28(4):766-779. doi:10.1038/s41591-022-01680-y 4 Morteau O, Gerard C, Lu B, et al. An indispensable role for the chemokine receptor CCR10 in IgA antibody-secreting cell accumulation. J Immunol. 2008;181(9):6309-6315. doi:10.4049/jimmunol.181.9.6309 Conflict of interest: Dr. Schramm, Sebastian: No conflict of interest Dedden, Mark: No conflict of interest Atreya, Raja: RA has served as a speaker, or consultant, or received research grants from AbbVie, Abivax, AlfaSigma, Arena Pharmaceuticals, Astra-Zeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion Healthcare, Dr Falk Pharma, Galapagos, Gilead, GlaxoSmithKline, InDex Pharmaceuticals, Johnson & Johnson, Lilly, Materia Prima, Merck Sharpe & Dohme, Pfizer, Roche Pharma, Takeda Pharma, Viatris. Zundler, Sebastian: S.Z. received speaker’s fees from Takeda, Roche, Galapagos, Ferring, Lilly, Falk and Janssen. S.Z. received research support from Takeda, Shire (a part of Takeda) and Roche.
Schramm et al. (2026) studied this question.