β7 integrins are required to give rise to intestinal mononuclear phagocytes with tolerogenic potential

Abstract

Mice lacking β7 integrins in the innate immune compartment are more susceptible to intestinal inflammation, which is correlated with a requirement of β7 integrins to reconstitute gut mononuclear phagocytes with tolerogenic potential.

Regulatory T-cell depletion in the gut caused by integrin β7 deficiency exacerbates DSS colitis by evoking aberrant innate immunity

“…37 Using T-cell transfer model of chronic colitis, Villablanca et al 37 showed that T cell-mediated colitis was aggravated in Itgb7 À / À Rag2 À / À mice compared with Rag2 À / À mice because of the impaired homing of mononuclear phagocytes to the gut, indicating a protective role of mononuclear phagocytes in chronic colitis. Taken together, mononuclear phagocytes might have distinct roles in inflammatory response in the gut under different conditions.…”

α4β7integrin: beyond T cell trafficking

“…2 The vitamin A metabolite retinoic acid (RA), produced by CD103 DCs via the enzyme retinaldehyde dehydrogenase 2 (encoded by Aldh1a2 gene), acting on T cells plays a critical role in this intestinal imprinting, 3 and DCs with this capacity can be identified by an assay that detects this enzymatic activity (ALDE + ). 4 Pharmacological intervention in tissuespecific recruitment of T cells has the potential advantage of very precise therapeutic intervention at the site of inflammation. 5 This theoretical promise that stemmed from fundamental work and preclinical model systems was indeed upheld.…”

“…A paper by Mora and colleagues elegantly highlights that α 4 β 7 integrins have important roles in innate immune cells as well, and that α 4 β 7 is required to mediate an important tolerogenic function of the mucosal immune system. 4 While blockade of α 4 β 7 integrin in immunodeficient, lymphopenic mice transferred with CD45RB high T cells has previously been shown to prevent colitis, 12 transfer of CD45RB high T cells into hosts that genetically lack β 7 integrin surprisingly accelerated colitis, 4 implying a protective role of this gut-homing integrin in the innate immune system. Notably, in a series of elegant competitive reconstitution experiments, the authors demonstrated that β 7 expression on bone marrow precursors was required to locate tolerogenic CD11c DCs, identified by their capacity to metabolise vitamin A as identified by the ALDEfluor assay, in Peyer's patches, small intestinal lamina propria and mesenteric lymph nodes, but β 7 was surprisingly not required for colonic DC reconstitution.…”

“…Notably, in a series of elegant competitive reconstitution experiments, the authors demonstrated that β 7 expression on bone marrow precursors was required to locate tolerogenic CD11c DCs, identified by their capacity to metabolise vitamin A as identified by the ALDEfluor assay, in Peyer's patches, small intestinal lamina propria and mesenteric lymph nodes, but β 7 was surprisingly not required for colonic DC reconstitution. 4 The authors were able to delineate a Lin neg Ly6C low population of bone marrow cells that expressed α 4 β 7 integrin, and which gave rise to a DC population with the capacity to produce RA, required for imprinting the gut-homing characteristics on T cells 3 4 (figure 1). Interestingly, RA was also required for the generation of these α 4 β 7 + Lin neg Ly6C low bone marrow precursor cells, albeit it is not yet known what cellular source of RA within the bone marrow is required for this function.…”

“…Interestingly, RA was also required for the generation of these α 4 β 7 + Lin neg Ly6C low bone marrow precursor cells, albeit it is not yet known what cellular source of RA within the bone marrow is required for this function. 4 Finally, via the demonstration of interleukin 10 induction in ovalbumin-transgenic T cells, the authors show that β 7 integrins on bone marrow precursors are required for the differentiation of gut-associated CD11c DCs with tolerogenic potential. 4 Although these insights were generated in mice that genetically lack only the β 7 chain of the α 4 β 7 integrin, the case made by the authors is compelling that the functional integrin necessary for this function is indeed the α 4 β 7 heterodimer 4 ; the alternative heterodimer, α E β 7 , has not been shown to mediate homing to the intestine, nor do α E knockout mice exhibit a defect in DC numbers or function.…”