Compromised intestinal epithelial barrier induces adaptive immune compensation that protects from colitis

• Type of Material: Article
• Authors: Manirath Khounlotham, Emory University; Wooki Kim, Emory University; Eric Peatman, Auburn University; Porfirio Nava, Emory University; Oscar Medina-Contreras, Emory University; Caroline Addis, Emory University; Stefan Koch, Emory University; Benedicte Fournier, Emory University; Asma Nusrat, Emory University; Timothy Denning, Emory University; Charles Parkos, Emory University
• Language: English
• Date: 2012-09-21
• Publisher: Elsevier (Cell Press)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Elsevier Inc.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.immuni.2012.06.017
• Title of Journal or Parent Work: Immunity
• ISSN: 1074-7613
• Volume: 37
• Issue: 3
• Start Page: 563
• End Page: 573
• Grant/Funding Information: This work was supported by grants from the NIH (DK061379 and DK72564 to C.A.P.; DK055679 and DK59888 to A.N.; and AA017870 and AI083554 to T.L.D.), core support from a Digestive Diseases Minicenter grant (DK 064399), a Emory Egleston Children’s Research Center seed grant to T.L.D., a Crohn’s and Colitis Foundation of America Career Development Award and an AGA Foundation for Digestive Health and Nutrition Research Scholar Award to P.N., and Crohn’s and Colitis Foundation of America Research Fellowship and senior research awards to M.K and B.F, respectively.
• Research Categories: Health Sciences, Pathology; Biology, Cell; Health Sciences, Immunology

Abstract

Mice lacking Junctional Adhesion Molecule A (JAM-A, encoded by F11r) exhibit enhanced intestinal epithelial permeability, bacterial translocation, and elevated colonic lymphocyte numbers, yet do not develop colitis. To investigate the contribution of adaptive immune compensation in response to increased intestinal epithelial permeability, we examined the susceptibility of F11r-/-Rag1-/- mice to acute colitis. Although negligible contributions of adaptive immunity in F11r-/-Rag1-/- mice were observed, F11r-/-Rag1-/- mice exhibited increased microflora-dependent colitis. Elimination of T cell subsets and cytokine analyses revealed a protective role for TGF-β-producing CD4+ T cells in F11r-/- mice. Additionally, loss of JAM-A resulted in elevated mucosal and serum IgA that was dependent upon CD4+ T cells and TGF-β. Absence of IgA in F11r+/+Igha-/- mice did not affect disease whereas F11r-/-Igha-/- mice displayed markedly increased susceptibility to acute injury induced colitis. These data establish a role for adaptive immune mediated protection from acute colitis under conditions of intestinal epithelial barrier compromise.