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 αEβ7 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 αEβ7 activation, but led to the depletion of αEβ7+ lymphocytes in the spleen and a significantly reduced population of αEβ7+ 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.

中文翻译：

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阻断整联蛋白α4β7激活的突变可防止适应性免疫介导的结肠炎，而不会增加对先天性结肠炎的敏感性。

β7整联蛋白负责从血液中有效募集淋巴细胞并将其保留在肠道相关的淋巴组织中。整联蛋白α4β7结合MAdCAM-1，在不活动时介导淋巴细胞在血管壁上的滚动粘附，在激活时介导牢固的粘附，从而控制了淋巴细胞归巢至肠道的两个关键步骤。相反，整联蛋白αEβ7通过与E-钙粘着蛋白相互作用而介导淋巴细胞与肠上皮细胞的粘附。整合素β7阻断抗体已在炎症性肠病（IBD）的临床管理中显示出功效；然而，完全阻断β7的功能会导致结肠调节性T（Treg）细胞耗竭，并通过引起异常的先天免疫而加剧硫酸葡聚糖硫酸钠（DSS）诱导的结肠炎，这暗示其对IBD管理的潜在不利影响。从而，需要一种针对整联蛋白β7的更好的治疗策略，以避免这种不良反应。在此，我们通过在小鼠体内携带整合素β7基因携带一个突变（F185A），从而抑制了整合素α4β7的激活，该突变（F185A）从结构研究中可以将α4β7锁定在其静止状态。来自β7-F185A敲入（KI）小鼠的淋巴细胞表达的α4β7整联蛋白不能被趋化因子激活，并显着损害肠道的归巢。β7-F185A突变不会抑制αEβ7活化，但会导致脾脏中的αEβ7+淋巴细胞耗竭，并且会导致KI小鼠肠道中的αEβ7+淋巴细胞数量显着减少。β7-F185AKI小鼠对T细胞转移诱导的慢性结肠炎有抗药性，但对DSS诱导的先天性结肠炎没有显示出增加的敏感性，这是完全阻断β7功能的不利影响。