β7 Gives Tregs a Gut Area Code

Abstract

iologics have revolutionized the treatment of inBflammatory bowel diseases (IBDs), which include Crohn’s disease and ulcerative colitis. Although many biologics (eg, infliximab) are targeted against tumor necrosis factor, blocking of lymphocyte-expressed integrins represents an important and widely used alternative. Vedolizumab is a key weapon in the therapeutic arsenal and consists of a humanized monoclonal antibody that binds heterodimeric a4b7 integrins, which are expressed primarily on lymphocytes that home to gut lymphoid and mucosal tissue. Blocking the extravasation of T lymphocytes, through inhibition of the interaction between a4b7 integrins and their endothelial receptor mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), prevents Tcell intestinal infiltration and inflammation in IBD, while sparing the patient of systemic immunosuppression, because the a4b7 integrin target is not expressed in immune cells that home to other organs. Vedolizumab improves IBD symptoms and induces remission in many patients, including in those who have not responded to other biologics. Despite the promise of a4b7-targeted therapies, the use of vedolizumab, similar to many other biologics, is associated with a high rate of clinical nonresponse. The reasons for this nonresponse are generally not known. There could be technical issues related to dosing and human variation in drug pharmacokinetics. However, could there be a deeper reason? In this issue, Sun et al show that genetic ablation of b7 integrin (Itgb7), one half of the integrin heterodimer inhibited by vedolizumab, paradoxically worsens colitis in mice. Understanding this phenomenon, and the role of b7 in the body, could help to build a biological framework to explain why some patients either do not respond or actually fare worse with vedolizumab. The findings are replicated in 2 different mouse models of colitis. The first, the Il10 model, involves the genetic deletion of the immunosuppressive cytokine interleukin 10 (IL10). IL10 is secreted by immunoregulatory cell types, including regulatory T cells (Tregs) and M2-polarized macrophages, and its loss predisposes animals to spontaneous, microbiome-targeted colitis. Sun et al have shown that the Il10 Itgb7 mice have reduced numbers of colonic Tregs relative to Il10 Itgb7þ/þ mice. The immunosuppressive function in vitro and homing of Itgb7 Tregs to other organs in vivo appeared normal, suggesting that b7-mediated homing of Tregs to the gut is needed to prevent severe disease. To support this phenomenon in an adoptive transfer colitis model with functional IL10, Sun et al co-transferred naive CD4þ conventional T cells and b7-expressing or b7-deficient Tregs to Rag1(ie, T-cell– and B-cell–) deficient recipients. A key advantage of the adoptive transfer model