Divergent cell cycle kinetics underlie the distinct functional capacity of mucosal T cells in Crohn's disease and ulcerative colitis

Abstract

Background: Different abnormalities of T cell effector function distinguish Crohn's disease (CD) from ulcerative colitis (UC). Because cell cycling determines effector function, pathogenic events in CD and UC may depend on cell cycle changes unique to each condition. Methods: Cell cycle kinetics, cycle regulatory molecule expression, apoptosis, caspase and telomerase activity, and cellular expansion were evaluated in CD2 and CD3 activated control, CD, and UC lamina propria T cells. Results: Compared with normal cells, CD T cells cycle faster, express increased phosphorylated Rb and decreased phosphorylated p53 levels, display less caspase activity but more telomerase activity, die less, and undergo vigorous cellular expansion. In contrast, UC T cells cycle slower, express normal levels of phosphorylated Rb and p53, display more caspase activity but have no telomerase activity, die more, and have a limited capacity to expand. Conclusions: T cell cycle abnormalities in CD indicate a state of hyperreactivity compatible with loss of tolerance, but a hyporeactive state compatible with anergy in UC. Thus distinct and divergent T cell cycle characteristics underlie the pathogenesis of the two main forms of inflammatory bowel disease.

Mesenchymal cell proliferation and programmed cell death: key players in fibrogenesis and new targets for therapeutic intervention

“…In the above mentioned study by Ina et al (24), less apoptosis occurred in CD than control T cells upon IL-2 deprivation, a difference that could be explained by the marked decrease in the proapoptotic protein bax and an increase in the antiapoptotic protein bcl-2 found in the CD T cell population. In keeping with these results, Sturm et al (72) showed that CD T cells display less caspase activity, but more telomerase activity, resulting in a significantly decreased rate of programmed cell death. More recently, it has been demonstrated that FAS-mediated apoptosis was lower in CD than in UC and control T cells, whereas enhanced expression of both long and short Flip (a Flice inhibitor protein) isoforms was present in both biopsy specimens and purified mucosal T cells taken from CD patients.…”

Escherichia coli Strain Nissle 1917 Ameliorates Experimental Colitis via Toll-Like Receptor 2- and Toll-Like Receptor 4-Dependent Pathways

“…In IBD, T cells expand in an uncontrolled fashion, causing mucosal inflammation (63). We have previously demonstrated that E. coli Nissle 1917 supernatants inhibit T-cell cycling and expansion via the TLR-2 receptor pathway (64).…”

IL-21 comes of age as a regulator of effector T cells in the gut

“…However, the absolute number of CD4 + T cells present in the gut mucosa of IBD patients is also due to an enhanced rate of cell cycling in CD. 5 There is a higher proliferation rate of CD4 + T cells isolated from the gut of CD patients compared to UC or normal controls. At an intracellular level, the high proliferation rate observed in CD CD4 + T cells is associated with an increased phosphorylation of Rb, which promotes the entry into the S phase of the cell cycle, and decreased phosphorylation of p53, a suppressor of S phase transit.…”