Intestinal inflammation in Gimap5 deficient mice: a possible link between loss of FoxO expression and impaired Treg function (104.18)

Abstract

Abstract We previously identified an N-ethyl-N-nitrosourea (ENU) induced mutant, sphinx, which lacks CD8+ T cells and natural killer cells in the peripheral lymphoid organs due to a recessive mutation in Gimap5 gene. Gimap5sph/sph mice developed spontaneous intestinal inflammation that is dependent on CD4+ T cells and commensal microflora. Gimap5sph/sph CD4+ T cells displayed a progressive lymphopenia, adopted a CD44hi CD62Llow activated phenotype and produced increased levels of IL-17. Lymphopenia of CD4+ T cells was accompanied with the progressive loss of FoxO1 and FoxO3 proteins. FoxO transcription factors have recently been implicated in regulatory T cell (Treg) development and function. Here we show that Gimap5sph/sph CD4+ T cells had a selective decline of the FoxP3+ Treg subset with time. Moreover, immune suppressive capacity of Gimap5sph/sph Treg cells was impaired in correlation with the loss of FoxO proteins. Further, adoptive transfer of wild type Treg cells into Gimap5sph/sph mice prevented the development of intestinal inflammation. Together, these results show a possible link between impaired homeostasis of T cells, particularly the Treg subset and loss of FoxO proteins which leads to intestinal inflammation in the absence of Gimap5 function.