Development of Inflammatory Bowel Disease in Long-Evans Cinnamon Rats Based on CD4+CD25+Foxp3+ Regulatory T Cell Dysfunction

Abstract

A mutant strain with defective thymic selection of the Long-Evans Cinnamon (LEC) rat was found to spontaneously develop inflammatory bowel disease (IBD)-like colitis. The secretion of Th1-type cytokines including IFN-γ and IL-2 from T cells of mesenteric lymph node cells (MLNs) and lamina propria mononuclear cells, but not spleen cells, in LEC rats was significantly increased more than that of the control Long-Evans Agouti rats through up-regulated expression of T-bet and phosphorylation of STAT-1 leading to NF-κB activation. In addition, the number of CD4+CD25+Foxp3+ regulatory T (Treg) cells of the thymus, MLNs, and lamina propria mononuclear cells from LEC rats was significantly reduced, comparing with that of the control rats. Moreover, bone marrow cell transfer from LEC rats into irradiated control rats revealed significantly reduced CD25+Foxp3+ Treg cells in thymus, spleen, and MLNs compared with those from control rats. Indeed, adoptive transfer with T cells of MLNs, not spleen cells, from LEC rats into SCID mice resulted in the development of inflammatory lesions resembling the IBD-like lesions observed in LEC rats. These results indicate that the dysfunction of the regulatory system controlled by Treg cells may play a crucial role in the development of IBD-like lesions through up-regulated T-bet, STAT-1, and NF-κB activation of peripheral T cells in LEC rats.

A Novel Role for TL1A/DR3 in Protection against Intestinal Injury and Infection

“…It is possible that ligand availability may be of pivotal importance under such conditions. In a previous study, TL1A-Ig augmented TCR-mediated proliferation of Foxp3 + Tregs, while at the same time, inhibited their suppressive capacity (48). Nevertheless, suppressive function was fully established in ex vivo Tregs upon removal of TL1A from the culture conditions.…”

“…These opposite results may be explained by the dichotomous role of TL1A /DR3 in acute versus chronic inflammatory conditions. Nevertheless, an imbalance between Tregs and Th17 cells has been reported in both IBD and experimental colitis (48, 49). …”

The effects of Foxp3-expressing regulatory T cells expanded with CD28 superagonist antibody in DSS-induced mice colitis

“…CD4+Foxp3+Treg cells play a critical role in the maintenance of self tolerance, control of autoimmune diseases, transplant rejection and have also been documented to offer a therapeutic option in severe inflammatory colitis [5,8,[17][18][19][20]. Therefore, therapeutic agents that are capable of enhancing the number and activity of this T-cell subset are highly desirable.…”

A potential role for regulatory T-cells in the amelioration of DSS induced colitis by dietary non-digestible polysaccharides

“…Treg are able to suppress, via different mechanisms, many aspects of the immune responses [31]. They have been indicated to modulate the severity of inflammatory colitis [32][33][34][35][36]. Furthermore, in commensal bacteria-colonized mice it has been shown that particularly the IL-10 production by Treg cells plays a critical role in maintaining intestinal homeostasis.…”