Protein phosphatase 4 (PP4) is essential during early T cells development. To assess the function of PP4 in peripheral T cells, we generated conditional PP4 knockout mice with CD4-cre transgene (CD4cre-PP4f/f). In these mice a partial block of thymocyte development was manifested as a ~40-60% reduction of peripheral T cells. Further studies showed that PP4 deletion resulted in poor T cell proliferation, inefficient Treg polarization, decreased Treg cell number and reduced Treg suppression activity. In vivo, CD4cre-PP4f/f mice exhibited defective T-dependent antibody production. More interestingly, by 5-month old ~50% of the CD4cre-PP4f/f mice developed spontaneous colitis with wasting syndrome, and showed increased percentages of IFNgamma+, IL-6+, or IL-17A+-producing cells in intra-epithelial lymphocytes and lamina propria lymphocytes. When investigating the pathogenesis of colitis, we found that transferring PP4-deficient CD4+CD45RBhigh cells failed to induce colitis in RAG-/- recipients, whereas antibiotics treatment could reverse the wasting syndrome. Combined with the defects in Treg and antibody production, these results are consistent with the possibility that PP4 deficiency reduced the efficiency of mucosal immunity against commensal bacteria, causing uncontrolled gut inflammation that eventually develop into colitis. The spontaneous colitis in CD4cre-PP4f/f mice may thus serve as an unique model for studying the pathogenesis of human inflammatory bowel disease.
Date:
2012-05
Relation:
Journal of Immunology. 2012 May;188(Suppl):120.14.
