Abstract
Although the etiology of Crohn's disease (CD) remains elusive this disease is characterized by T cell activation that leads to chronic inflammation and mucosal damage. A potential role for maladaptation between the intestinal microbiota and the mucosal immune response is suggested by the fact that mutations in the pattern recognition receptor Nod2 are associated with higher risks for developing CD. Although Nod2 deletion in CD4+ T cells has been shown to impair the induction of colitis in the murine T cell transfer model, the analysis of T cell intrinsic Nod2 function in T cell differentiation and T cell-mediated immunity is inconsistent between several studies. In addition, the role of T cell intrinsic Nod2 in regulatory T cell (Treg) development and function during colitis remain to be analyzed. In this study, we show that Nod2 expression is higher in activated/memory CD4+ T cells and its expression was inducible after T cell receptor (TCR) ligation. Nod2 stimulation with muramyl dipeptide (MDP) led to a nuclear accumulation of c-Rel NF-kB subunit. Although functionally active in CD4+ T cells, the deletion of Nod2 did not impair the induction and the prevention of colitis in the T cell transfer model. Moreover, Nod2 deletion did not affect the development of Foxp3+ Treg cells in the spleen of recipient mice and Nod2 deficient CD4 T cells expressing the OVA specific transgenic TCR were able to differentiate in Foxp3+ Treg cells after OVA feeding. In vitro, CD25+ Nod2 deficient T cells suppressed T cell proliferation as well as wild type counter parts and T cell stimulation with MDP did not affect the proliferation and the cytokine secretion of T cells. In conclusion, our data indicate that Nod2 is functional in murine CD4+ T cells but its expression is dispensable for the T cell regulation of colitis.
Highlights
The intestinal mucosa is exposed to a large number and variety of commensal microorganisms
Nod2 protein expression was increased after splenic CD4+ T cell stimulation with anti-CD3 and antiCD28 monoclonal antibodies, indicating that T cell receptor (TCR) ligation regulates T cell intrinsic Nod2 expression (Figure 1A)
Nod2 mRNA level was significantly higher in activated/memory T cells compared to naive T cells, no differences were observed between Foxp3- and Foxp3+ activated/memory T cell subsets (Figure 1B)
Summary
The intestinal mucosa is exposed to a large number and variety of commensal microorganisms In pathological conditions such as inflammatory bowel diseases (IBDs), an abnormal immune response towards commensal bacteria can contribute to mucosal inflammation. Crohn’s disease (CD) is characterized by activation of T cells that produce inflammatory cytokines and contribute to intestinal inflammation and mucosal barrier destruction. This abnormal inflammatory response is thought to result from the effect of environmental or microbial activation of the local immune response in a genetically predisposed host [1,2].
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