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.

Objective. Recently, 2 classes of cytokine inhibitors have been defined at the molecular level. The largest group comprises the extracellular domains of cell surface cytokine receptors, and includes both tumor necrosis factor receptors (TNF‐R). The present study was conducted to investigate the role of TNF inhibitors in arthritis.Methods. We measured p55 and p75 soluble TNF‐R (sTNF‐R) in serum and synovial fluid (SF) samples from patients with rheumatic diseases and compared their levels with levels of soluble interleukin‐2 receptors (sIL‐2R). Sensitive enzyme‐linked immunosorbent assays (ELISA), specific for p55 and p75 sTNF‐R and for sIL‐2R, were used.Results. Serum levels of p75 sTNF‐R were 3–4‐fold higher than levels of p55 sTNF‐R, and both were significantly elevated in patients with osteoarthritis (OA) and rheumatoid arthritis (RA) compared with healthy controls. RA SF levels of sTNF‐R were 4–5‐fold higher than levels in serum, suggesting local production in the joint, and were significantly higher than levels in the SF of patients with seronegative arthropathy or OA. Furthermore, levels of p55 and p75 sTNF‐R, but not sIL‐2R or TNFα measured by ELISA, were increased in the SF of patients with clinically active RA. The soluble TNF‐R in RA and OA SF were functional since they inhibited TNF activity in a cytotoxicity assay in proportion to the levels of inhibitor present. Evaluation of serially obtained serum samples suggested that sTNF‐R may be a useful parameter for monitoring RA disease activity.Conclusion. Biologically active soluble TNF‐R are up‐regulated in patients with rheumatic disease and are produced locally in the joints. Measurement of serum levels of TNF‐R may be useful for monitoring of disease, and determination of SF levels could be of diagnostic value.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. Current therapies, such as corticosteroids, immunosuppressants, and anti–tumor necrosis factor (TNF) antibodies, are not universally effective at induction and maintenance of remission,¹ x 1 Ordas, I., Eckmann, L., Talamini, M. et al. Ulcerative colitis. Lancet. 2012; 380: 1606–1619 Abstract | Full Text | Full Text PDF | PubMed | Scopus (466) | Google Scholar See all References with ≈25% of patients requiring colectomy.² x 2 Bach, S.P. and Mortensen, N.J. Ileal pouch surgery for ulcerative colitis. World J Gastroenterol. 2007; 13: 3288–3300 Crossref | PubMed | Scopus (50) | Google Scholar See all References This variable response to treatment and disease progression may reflect significant heterogeneity in disease pathobiology.³ x 3 Ananthakrishnan, A.N. Personalizing therapy for inflammatory bowel diseases. Expert Rev Gastroenterol Hepatol. 2013; 7: 549–558 Crossref | PubMed | Scopus (5) | Google Scholar See all References ^{, 4} x 4 Loftus, E.V. Jr., Davis, K.L., Wang, C.C. et al. Treatment patterns, complications, and disease relapse in a real-world population of patients with moderate-to-severe ulcerative colitis initiating immunomodulator therapy. Inflamm Bowel Dis. 2014; 20: 1361–1367 Crossref | PubMed | Scopus (2) | Google Scholar See all References Improved stratification driven by patient heterogeneity may help guide choice of therapeutic intervention and enhance efficacy and safety.