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Background  The Fas pathway is a major regulator of T cell homeostasis, however, the T cell population that is controlled by the Fas pathway in vivo is poorly defined. Although CD4 and CD8 single positive (SP) T cells are the two major T cell subsets in the periphery of wild type mice, the repertoire of mice bearing loss-of-function mutation in either Fas (lpr mice) or Fas ligand (gld mice) is predominated by CD4 − CD8 −  double negative αβ T cells that also express B220 and generally referred to as B220 + DN T cells. Despite extensive analysis, the basis of B220 + DN T cell lymphoproliferation remains poorly understood. In this study we re-examined the issue of why T cell lymphoproliferation caused by gld mutation is predominated by B220 + DN T cells.    Methodology and Principal Findings  We combined the following approaches to study this question: Gene transcript profiling, BrdU labeling, and apoptosis assays. Our results show that B220 + DN T cells are proliferating and dying at exceptionally high rates than SP T cells in the steady state. The high proliferation rate is restricted to B220+DN T cells found in the gut epithelium whereas the high apoptosis rate occurred both in the gut epithelium and periphery. However, only in the periphery, apoptosis of B220 + DN T cell is Fas-dependent. When the Fas pathway is genetically impaired, apoptosis of peripheral B220 + DN T cells was reduced to a baseline level similar to that of SP T cells. Under these conditions of normalized apoptosis, B220 + DN T cells progressively accumulate in the periphery, eventually resulting in B220 + DN T cell lymphoproliferation.    Conclusions/Significance  The Fas pathway plays a critical role in regulating the tissue distribution of DN T cells through targeting and elimination of DN T cells from the periphery in the steady state. The results provide new insight into pathogenesis of DN T cell lymphoproliferation.

Fas-Mediated Apoptosis Regulates the Composition of Peripheral αβ T Cell Repertoire by Constitutively Purging Out Double Negative T Cells