Many body surfaces harbor organ-specific γδ T cell compartments that contribute to tissue integrity. Thus, murine dendritic epidermal T cells (DETCs) uniquely expressing T cell receptor (TCR)-Vγ5 chains protect from cutaneous carcinogens. The DETC repertoire is shaped by Skint1, a butyrophilin-like (Btnl) gene expressed specifically by thymic epithelial cells and suprabasal keratinocytes. However, the generality of this mechanism has remained opaque, since neither Skint1 nor DETCs are evolutionarily conserved. Here, Btnl1 expressed by murine enterocytes is shown to shape the local TCR-Vγ7+ γδ compartment. Uninfluenced by microbial or food antigens, this activity evokes the developmental selection of TCRαβ+ repertoires. Indeed, Btnl1 and Btnl6 jointly induce TCR-dependent responses specifically in intestinal Vγ7+ cells. Likewise, human gut epithelial cells express BTNL3 and BTNL8 that jointly induce selective TCR-dependent responses of human colonic Vγ4+ cells. Hence, a conserved mechanism emerges whereby epithelia use organ-specific BTNL/Btnl genes to shape local T cell compartments.

The COVID-19 pandemic is putting unprecedented pressures on healthcare systems globally. Early insights have been made possible by rapid sharing of data from China and Italy. In the UK, we have rapidly mobilised inflammatory bowel disease (IBD) centres in order that preparations can be made to protect our patients and the clinical services they rely on. This is a novel coronavirus; much is unknown as to how it will affect people with IBD. We also lack information about the impact of different immunosuppressive medications. To address this uncertainty, the British Society of Gastroenterology (BSG) COVID-19 IBD Working Group has used the best available data and expert opinion to generate a risk grid that groups patients into highest, moderate and lowest risk categories. This grid allows patients to be instructed to follow the UK government’s advice for shielding, stringent and standard advice regarding social distancing, respectively. Further considerations are given to service provision, medical and surgical therapy, endoscopy, imaging and clinical trials.

Murine intraepithelial γδ T cells include distinct tissue-protective cells selected by epithelial butyrophilin-like (BTNL) heteromers. To determine whether this biology is conserved in humans, we characterized the colonic γδ T cell compartment, identifying a diverse repertoire that includes a phenotypically distinct subset coexpressing T cell receptor Vγ4 and the epithelium-binding integrin CD103. This subset was disproportionately diminished and dysregulated in inflammatory bowel disease, whereas on-treatment CD103 ⁺ γδ T cell restoration was associated with sustained inflammatory bowel disease remission. Moreover, CD103 ⁺ Vγ4 ⁺ cell dysregulation and loss were also displayed by humans with germline BTNL3/BTNL8 hypomorphism, which we identified as a risk factor for penetrating Crohn’s disease (CD). Thus, BTNL-dependent selection and/or maintenance of distinct tissue-intrinsic γδ T cells appears to be an evolutionarily conserved axis limiting the progression of a complex, multifactorial, tissue-damaging disease of increasing global incidence.

Purpose.: First, to determine whether tumor necrosis factor-(TNF)-α is expressed in the conjunctiva of ocular mucous membrane pemphigoid (MMP) and the consequences of systemic immunosuppressive treatment on this expression. Second, to investigate the in vitro effects of TNFα on human conjunctival fibroblasts. Methods.: The expression of TNFα in conjunctival tissues of patients with actively inflamed ocular MMP (n = 10), patients with clinically noninflamed ocular MMP after systemic immunosuppressive treatment (n = 10), and normal subjects (n = 10) was studied by immunohistochemistry. The effect of TNFα on functional assays of human conjunctival fibroblast activity were investigated, including migration, collagen lattice contraction, matrix metalloproteinase (mmp), and tissue inhibitor of matrix metalloproteinase (timp) secretion, proliferation, and surface expression of HLA-DR, ICAM, CD80, CD86, CD40, CD40-ligand. Results.: In active ocular MMP, TNFα is expressed by a large number of stromal infiltrating cells (234 cells/mm²), and although the level of stromal TNFα expression is significantly reduced after immunosuppressive treatment (90 cells/mm²), these levels are still significantly elevated compared with normal conjunctiva (10 cells/mm², P < 0.05). TNFα stimulates increased migration by conjunctival fibroblasts (P < 0.001), increased production of mmp-9 (P = 0.01), decreased production of timp-2 (P = 0.01) and timp-4 (P = 0.04), and upregulated expression of CD40 and ICAM (P = 0.04). No significant effects of TNFα on fibroblast proliferation or collagen lattice contraction were detected. Conclusions.: Increased conjunctival expression of TNFα in ocular MMP suggests that systemic TNFα antagonists are likely to be effective in controlling severe disease unresponsive to conventional systemic immunosuppression. Residual TNFα expression persists in clinically noninflamed disease. TNFα appears to have profibrotic and proinflammatory effects on human conjunctival fibroblasts.