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Compromised intestinal barrier induces adaptive immune responses that protect from colitis
Author(s) -
Khounlotham Manirath,
Kim Wooki,
Peatman Eric,
Koch Stefan,
Nava Porfirio,
Medina-Contreras Oscar,
Nusrat Asma,
Denning Timothy L,
Parkos Charles A
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.136.6
Subject(s) - colitis , immune system , acquired immune system , intestinal permeability , immunology , immunity , inflammation , biology , mucosal immunology , t cell , intestinal mucosa , medicine
Mice lacking Junctional Adhesion Molecule A (JAM‐A) exhibit enhanced intestinal permeability, bacterial translocation, and elevated numbers of colonic T and B cells and IgA, yet do not develop colitic disease. To study whether enhanced adaptive immunity compensates for increased intestinal permeability, we examined susceptibility of Jam‐a −/− Rag −/− mice to acute, injury‐induced colitis. Data revealed negligible contribution of adaptive immunity in mice with intact epithelial barriers; however Jam‐a −/− Rag −/− mice exhibited dramatically increased microflora‐dependent colitis compared to Jam‐a −/− controls. Specific depletion of T cells and neutralization of TGFβ revealed a protective role for TGFβ‐producing CD4 T cells in Jam‐a −/− but not Jam‐a +/+ mice. A major mechanism of TGFβ‐producing CD4 T cell‐mediated protection was via increased IgA production and consistent with this observation, Jam‐a −/− Iga −/− mice displayed markedly increased colitis. These data delineate a critical protective pathway involving TGFβ‐producing CD4 T cell‐induced IgA in response to epithelial barrier defects and mucosal injury‐induced intestinal inflammation. These findings suggest that, under conditions of preexisting intestinal barrier compromise, adaptive immune mechanisms play an important compensatory role that protects from colitis. This work is supported by NIH grants DK061379, DK59888 and AA017870.