Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn’s disease, arises as a result of an abnormal response by the immune system to antigens in the gut, including food and trillions of commensal intestinal bacteria (those that under normal circumstances do not harm their host). The pathogenesis of the disease is still incompletely understood, but is thought to involve a complex interaction of genetic, environmental and immunoregulatory factors. A recent study in Cell & Bioscience by Tse-Hua Tan and Ching-Yu Huang from the Immunology Research Center, Taiwan, and colleagues, provides fresh insights into the development of IBD, implicating the role of protein phosphatase 4 (PP4) and its effect on the specialised immune cells, regulatory T (Treg) cells.
Treg cells play a vital role in maintaining a balanced immune system and establishing tolerance to foreign, non-pathogenic antigens by suppressing the immune response of other cells. They can be induced in peripheral tissues or produced from T cells in the thymus; in the latter case PP4 is thought to be essential. The authors set out to more deeply probe the functions of PP4 on Treg cells in vivo.
Treg cell development and function was assessed in the absence of PP4 by generating floxed PP4 mice, whereby the gene encoding PP4 was blocked specifically in T cells at the stage of repertoire selection in the thymus. They found that deletion of PP4 led to fewer Treg cells in both the thymus and peripheral tissues. Also, PP4-deficient Treg cells had reduced suppressor function, which was associated with a decrease in expression of the proteins IL-10, CTLA4, GITR and CD103, implicating these molecules as potential targets of PP4.
Notably, symptoms resembling human Crohn’s disease, namely colitis and inflammation of the small intestine, developed in approximately 60 percent of the T cell-specific, PP4-deficient mice, and was correlated with reduced numbers of Treg cells in the gut. This suggests that PP4 is essential for the maintenance of protective gut immunity. However, further analysis revealed that PP4-deficient Treg cells were still capable of suppressing experimental colitis, indicating that this aspect of Treg cell function remains viable. Other elements of immune development influenced by PP4 are therefore likely to be responsible for inducing spontaneous colitis in these mice, supporting the view that IBD is a multifactorial disease.
As the incidence and prevalence of IBD increases worldwide, the need to understand this condition becomes more pressing. These findings suggest an important role for PP4 in regulating the immune system via the modulation of Treg function and may provide a new perspective for future studies on IBD.
Protein phosphatase 4 is an essential positive regulator for Treg development, function, and protective gut immunity
Cell & Bioscience 2014, 4:25
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