A mutation that blocks integrin α(4)β(7) activation prevents adaptive immune-mediated colitis without increasing susceptibility to innate colitis

BACKGROUND: β(7) integrins are responsible for the efficient recruitment of lymphocytes from the blood and their retention in gut-associated lymphoid tissues. Integrin α(4)β(7) binds MAdCAM-1, mediating rolling adhesion of lymphocytes on blood vessel walls when inactive and firm adhesion when activated, thereby controlling two critical steps of lymphocyte homing to the gut. By contrast, integrin α(E)β(7) mediates the adhesion of lymphocytes to gut epithelial cells by interacting with E-cadherin. Integrin β(7) blocking antibodies have shown efficacy in clinical management of inflammatory bowel disease (IBD); however, fully blocking β(7) function leads to the depletion of colonic regulatory T (Treg) cells and exacerbates dextran sulfate sodium (DSS)-induced colitis by evoking aberrant innate immunity, implying its potential adverse effect for IBD management. Thus, a better therapeutic strategy targeting integrin β(7) is required to avoid this adverse effect. RESULTS: Herein, we inhibited integrin α(4)β(7) activation in vivo by creating mice that carry in their integrin β(7) gene a mutation (F185A) which from structural studies is known to lock α(4)β(7) in its resting state. Lymphocytes from β(7)-F185A knock-in (KI) mice expressed α(4)β(7) integrins that could not be activated by chemokines and showed significantly impaired homing to the gut. The β(7)-F185A mutation did not inhibit α(E)β(7) activation, but led to the depletion of α(E)β(7)(+) lymphocytes in the spleen and a significantly reduced population of α(E)β(7)(+) lymphocytes in the gut of KI mice. β(7)-F185A KI mice were resistant to T cell transfer-induced chronic colitis, but did not show an increased susceptibility to DSS-induced innate colitis, the adverse effect of fully blocking β(7) function. CONCLUSIONS: Our findings demonstrate that specific inhibition of integrin α(4)β(7) activation is a potentially better strategy than fully blocking α(4)β(7) function for IBD treatment.