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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.

A mutation that blocks integrin α4β7 activation prevents adaptive immune-mediated colitis without increasing susceptibility to innate colitis