Abstract
BackgroundThe 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 FindingsWe 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/SignificanceThe 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.
Highlights
The Fas receptor is the prototypical member of the tumor necrosis factor receptor (TNFR) family of cytokines and is constitutively expressed on T cells [1,2,3]
T cells in Fas ligand (FasL)-deficient gld mice double negative (DN) T cells gradually accumulate in periphery of mice bearing lpr mutation of Fas receptor or gld mutation of FasL leading to T cell lymphoproliferation
To rule out the possibility that some activated single positive (SP) T cells could have downregulated their coreceptors and persisted as DN T cells, we analyzed whether superantigen activation of Vb8-bearing SP T cells leads to long-term increase in Vb8-bearing DN T cells
Summary
The Fas receptor is the prototypical member of the tumor necrosis factor receptor (TNFR) family of cytokines and is constitutively expressed on T cells [1,2,3]. Massive numbers of a peculiar type of TCRab cells that is referred to as double negative (DN) T cells due to the lack of CD4 and CD8 coreceptors, gradually accumulate in the lymph nodes and spleens of mice with loss-of-function mutation in Fas (lpr) or Fas ligand (gld) leading to qualitative changes in the composition of peripheral T cell repertoire and to DN T cell lymphoproliferation [17,18,19] These DN T cells are positive for B220, an isoform of CD45 molecule that is normally expressed by B cells and are generally referred to as B220+. In this study we re-examined the issue of why T cell lymphoproliferation caused by gld mutation is predominated by B220+DN T cells
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