Fas-mediated apoptosis regulates the composition of peripheral alphabeta T cell repertoire by constitutively purging out double negative T cells

PLoS One. 2008;3(10):e3465. doi: 10.1371/journal.pone.0003465. Epub 2008 Oct 21.


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 alphabeta 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • CD4 Antigens
  • CD8 Antigens
  • Cell Proliferation
  • Fas Ligand Protein
  • Gene Expression Profiling
  • Leukocyte Common Antigens
  • Lymphocyte Count
  • Lymphoproliferative Disorders / etiology
  • Mice
  • Receptors, Antigen, T-Cell, alpha-beta*
  • T-Lymphocyte Subsets / cytology*
  • T-Lymphocytes
  • fas Receptor*


  • CD4 Antigens
  • CD8 Antigens
  • Fas Ligand Protein
  • Receptors, Antigen, T-Cell, alpha-beta
  • fas Receptor
  • Leukocyte Common Antigens