A subset of gut-intrinsic γδ T-cells have an evolutionarily conserved role in promoting intestinal tissue repair and homeostasis

Dart R, Zlatareva I, Vantourout P, et al. Conserved γδ T cell selection by BTNL proteins limits progression of human inflammatory bowel disease. Science 2023; doi: 10.1126/science.adh0301.

γδ T-cells are not major histocompatibility complex restricted, and can be selected for or maintained by T-cell receptor (TCR)-dependent interaction with organ-specific butyrophilin-like (BTNL) proteins expressed by epithelial cells. In mice, γδ T-cell repertoires appear to play a significant role in maintaining tissue homeostasis, with γδ T cell-deficient mice demonstrating susceptibility to experimental colitis. However, their role in humans, and in the pathogenesis of inflammatory bowel disease (IBD), has not previously been described.

In this study, the colonic γδ T-cell compartment was characterised in biopsies obtained from inflamed and uninflamed IBD tissue samples, and healthy control subjects. A distinct subset of γδ T-cells was identified, coexpressing TCR Vγ4 (V gamma 4) and the epithelium-binding integrin CD103 (cluster of differentiation 103, also known as αEβ7). These cells responded strongly to TCR-mediated selection signals provided by a BTNL3+BTNL8 protein heterodimer, but were less responsive to potent activating stimuli than αβ T-cells, producing less tumour necrosis factor-alpha, interferon gamma and interleukin 2. This CD103⁺ γδ T-cell subset was found to be reduced in frequency and dysregulated in both ulcerative colitis and Crohn’s disease (CD) subjects, with restoration of this population associated with sustained remission in those receiving treatment. Furthermore, a polymorphism which results in hypomorphic BTNL8*3 heterodimer protein production was identified as being associated with a severe penetrating CD phenotype. Dart et al, suggest that monitoring intestinal populations of Vγ4⁺ CD103⁺ γδ T-cells may be useful in assessing treatment response, and that targeting the BTNL-γδ axis in IBD treatment could promote tissue repair.

New genetic loci associated with metabolic dysfunction-associated steatotic liver disease give further insight into disease pathogenesis

Chen Y, Du X, Kuppa A, et al. Genome-wide association meta-analysis identifies 17 loci associated with non-alcoholic fatty …