Gene Regulatory Events in Establishing Mature T Cell Tolerance

National Institute Of Allergy And Infectious Diseases

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Abstract

Inborn errors of immunity (IEI) can affect global cellular regulatory systems. We concentrated on one project where IEI can cause devastating disease. G Protein-Coupled Receptor 15 (GPR15) is a chemokine receptor, primarily expressed in T cells based on human single-cell RNA sequencing data. Its natural ligand, GPR15L, is found in the gastrointestinal basal epithelial region and presumably guide GPR15+ T cells to that location. Previous studies showed that Gpr15 knockout mice were more susceptible to C. rodentium-induced colitis but the function of GPR15 and whether its deficiency plays a role in inflammatory bowel disease (IBD) in humans are unclear. We recruited three pediatric patients who developed severe early-onset IBD and found novel GPR15 mutations using whole-exome sequencing. A reduction in T cells was observed in patient colon biopsies. Surface staining of patient T cells after TCR stimulation further revealed low expression of the mutant GPR15 alleles compared to the wildtype. Characterizing the GPR15 mutants in transduced stable cell lines, we found that the mutations led to lower GPR15L-dependent signaling, causing decreased cell chemotaxis towards the ligand. Accordingly, Gpr15 knockout mouse colon also exhibited reduced T cell phenotype observed in patients. Our results indicate that GPR15 is critical for T cell migration to the human colon and its absence may lead to immunodeficiency in the region, predisposing individuals to IBD induced by specific pathogenic microbiota. Recent reports of pathogenic variants in NCKAP1L, a hematopoietically-restricted gene encoding the HEM1 protein component of the WAVE regulatory complex (WRC), defined a novel disease involving recurrent bacterial and viral infections, autoimmunity, and excessive inflammation (OMIM 141180). We have summarized the diverse clinical presentations and immunological phenotypes observed in HEM1-deficient patients. In addition, we integrate the pathophysiological mechanisms described in current literature and highlight the outstanding questions for diagnosis and management of the HEM1-immunodysregulatory disorder.