A mutation that blocks integrin α₄β₇ activation prevents adaptive immune-mediated colitis without increasing...

β₇ integrins are responsible for the efficient recruitment of lymphocytes from the blood and their retention in gut-associated lymphoid tissues. Integrin α₄β₇ 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_Eβ₇ mediates the adhesion of lymphocytes to gut epithelial cells by interacting with E-cadherin. Integrin β₇ blocking antibodies have shown efficacy in clinical management of inflammatory bowel disease (IBD); however, fully blocking β₇ 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 β₇ is required to avoid this adverse effect.

Herein, we inhibited integrin α₄β₇ activation in vivo by creating mice that carry in their integrin β₇ gene a mutation (F185A) which from structural studies is known to lock α₄β₇ in its resting state. Lymphocytes from β₇-F185A knock-in (KI) mice expressed α₄β₇ integrins that could not be activated by chemokines and showed significantly impaired homing to the gut. The β₇-F185A mutation did not inhibit α_Eβ₇ activation, but led to the depletion of α_Eβ₇⁺ lymphocytes in the spleen and a significantly reduced population of α_Eβ₇⁺ lymphocytes in the gut of KI mice. β₇-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 β₇ function.

Our findings demonstrate that specific inhibition of integrin α₄β₇ activation is a potentially better strategy than fully blocking α₄β₇ function for IBD treatment.