The Role of Integrin Beta7 on T Lymphocytes Trafficking during Intestinal Inflammation
- Author(s): Kuk, Wun
- Advisor(s): Ginsberg, Mark H;
- Sun, Hao
- et al.
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract including two major categories, Crohn’s disease (CD) and ulcerative colitis (UC). Rapid recruitment of lymphocytes from peripheral circulation to the gut mucosa is a key feature of IBD. The process of lymphocytes homing to the gut is a multiple-step adhesion
cascade that is mediated by adhesion molecules such as integrin α4β7. Integrin α4β7 is expressed on lymphocytes and interacts with its ligand, mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), which is primarily expressed in the high endothelial venules in the small intestine, the colon, and Peyer’s Patches. Integrin α4β7 is a therapeutic target in IBD. Clinical studies report that vedolizumab, a humanized antibody against integrin α4β7, effectively maintains clinical remission in IBD patients. However, aggravated colitis was observed in a small percentage of patients treated with high dose of vedolizumab, which is probably due to aberrant innate immune response to intestinal mucosal injury and infection. Here, the role of integrin β7 on recruiting conventional and regulatory T lymphocytes during intestinal inflammation is further investigated by using two IBD mouse models. Conventional/effector T cells activate other effector immune cells whereas regulatory T cells suppress inflammatory activities and maintain peripheral tolerance. The results demonstrated that deficiency in integrin β7 exacerbates induced spontaneous colitis. The suppression function of β7-deficient Treg cells remains intact. However, integrin β7-deficiency impairs the homing capacity of both regulatory T cells and effector T cells to the GALT. These findings possibly explain the adverse effects seen in high dose vedolizumab treatment, suggesting that excessive blocking of integrin β7 function should be avoided to prevent potential adverse effects of this medication.