Abstract
BackgroundMice deficient in the inhibitory G protein subunit Gαi2 spontaneously develop a T helper 1 dominated colitis. We examined whether a defect in CD4+FoxP3+ regulatory T cells (Treg) underpins the pathogenesis of colitis in the Gαi2−/− (Gαi2-deficient) colitis model.Methodology/Principal FindingsUsing flow cytometry, we found that thymus and colonic lamina propria, but not spleen and mesenteric lymph nodes, of colitic Gαi2−/− mice contained increased frequencies of Treg, whereas FoxP3 expression intensity was similar in Gαi2−/− compared to Gαi2+/− or Gαi2+/+ wild type (WT) mice. The frequency of CD4+FoxP3+ T cells expressing CD103 was significantly increased in Gαi2−/− compared to WT mice. Treg in colons from WT mice clustered in the T cell areas of colonic lymphoid patches (CLP), with relatively few Treg in the lamina propria, as demonstrated by immunohistochemistry. In Gαi2−/− mice, CLP were not observed but lamina propria Treg were increased in number and frequency within the CD4+ infiltrate, compared to WT mice. Using an in vitro co-culture system and flow cytometric analysis of cell division we could demonstrate that the in vitro suppressive function of WT and Gαi2−/− CD4+FoxP3+ regulatory T cells (WT-Treg and KO-Treg) was indistinguishable, but that T effector cells (CD4+25− T cells) from Gαi2−/− mice were less readily suppressed than WT effectors (WT-Teff) by Treg from either source. However, neither WT nor Gαi2−/− Treg was able to suppress colitis induced by adoptive transfer of Gαi2−/− effector T cells (KO-Teff) to RAG2−/− recipients. The enhanced inflammatory activity of Gαi2−/− effectors was accompanied by increased expression of an effector/memory T cell phenotype and increased cytokine secretion, especially IL-4, IL-6 and IFN-γ.ConclusionsThere is an increased frequency of Gαi2−/− Treg in the colon, and they demonstrate no endogenous functional defect. However, Gαi2−/− T effector cells are dramatically less susceptible to suppression in vitro, and in vivo, despite increased effective numbers of Treg, they cannot prevent disease.
Highlights
The mucosal immune dysregulation which results in chronic inflammatory bowel disease (IBD) has been evaluated using several chemically-induced, T cell transfer and spontaneous mouse models of colitis
There are two subsets of Treg: natural Treg, which develop in the thymus; and inducible Treg, which are derived from naıve CD4+ T cells in the periphery
Inducible Treg comprise type 1 regulatory T cells (Tr1), which are induced by IL-10 [12] and T helper 3 (Th3) cells, which are induced by TGFb [13]
Summary
The mucosal immune dysregulation which results in chronic inflammatory bowel disease (IBD) has been evaluated using several chemically-induced, T cell transfer and spontaneous mouse models of colitis. Untreated Gai22/2 mice on a 129SvEv background spontaneously develop colitis [1,2,3]. The development of colitis in the Gai22/2 mouse model is dependent on the presence of an enteric microflora (unpublished observations) and is characterized by a Th1 CD4+ T cell response, with increased production of IFN-c, together with increased levels of IL-1, IL-6 and TNF-a in inflamed tissue [1,2,4]. Peripheral immune tolerance is mediated by several mechanisms, including anergy; deletion; ignorance; or suppression of effector T cell (Teff) function by different populations of regulatory T cells (Treg) [11]. Mice deficient in the inhibitory G protein subunit Gai spontaneously develop a T helper 1 dominated colitis. We examined whether a defect in CD4+FoxP3+ regulatory T cells (Treg) underpins the pathogenesis of colitis in the Gai22/2 (Gai2-deficient) colitis model
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