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Intestinal epithelial barrier dysfunction induces IL‐17 production by γδ intraepithelial lymphocytes: A novel mechanism of mucosal tolerance
Author(s) -
Edelblum Karen L,
Turner Jerrold R
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.1155.3
Subject(s) - lamina propria , myosin light chain kinase , intraepithelial lymphocyte , foxp3 , microbiology and biotechnology , biology , cd8 , t cell , cytokine , immunology , t cell receptor , immune system , epithelium , chemistry , myosin , genetics
Myosin light chain kinase (MLCK) is essential for pathophysiological epithelial tight junction regulation. Transgenic (Tg) mice with intestinal epithelial‐specific expression of constitutively‐active MLCK (CA‐MLCK) demonstrate increased tight junction permeability and mucosal Th1 activation, but do not develop spontaneous disease. Therefore, we hypothesized that chronic luminal antigen exposure induces tolerance, which in turn prevents immune‐mediated disease in CA‐MLCK Tg mice. To identify underlying mechanisms, colonic intraepithelial and lamina propria T cell functions were assessed. CA‐MLCK expression increased lamina propria CD4 + and CD8 + , but not Foxp3 + , T cell numbers, suggesting that tolerance was not driven by Foxp3 + T regulatory cells. Further, cytokine production after ex vivo stimulation was similar in lamina propria CD8 + T cells, although slight increases in CD4 + T cell IL‐17 production were noted. In contrast, IL‐17 production by intraepithelial γδ TCR + , but not αβ TCR + , T cells was markedly increased in CA‐MLCK mice. Antibiotic treatment normalized IL‐17 production in CA‐MLCK Tg mice, suggesting that the epithelial barrier regulates microbial activation of Th17 responses. These data suggest that limited Th17 activation may dampen Th1 responses and thereby induce tolerance that prevents disease in the setting of chronic epithelial barrier dysregulation. Funding: AGA and NIH.