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.