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International Immunology Advance Access originally published online on April 13, 2004
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International Immunology, Vol. 16, No. 5, pp. 759-766, May 2004
© 2004 Japanese Society for Immunology

Changes in sensitivity of peripheral lymphocytes of autoimmune gld mice to FasL-mediated apoptosis reveal a mechanism for the preferential deletion of CD4–CD8–B220+ T cells

Sheng Xiao1,6, Xingmin Zhang4, Koren K. Mann1,5, Satoshi Jodo3, Li Li6, Wael N. Jarjour6, Ann Marshak-Rothstein2, David H. Sherr5 and Shyr-Te Ju1,6

1 Department of Pathology and Laboratory Medicine, 2 Department of Microbiology and 3 Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA 4 Center for Neurologic Diseases, Harvard Medical School, Boston, MA 02115, USA 5 Department of Environmental Health, School of Public Health, Boston University School of Medicine, Boston, MA 02118, USA 6 Department of Medicine, Division of Rheumatology and Immunology, University of Virginia, Charlottesville, VA 22908, USA

Correspondence to: S.-T. Ju; E-mail: sj8r{at}virginia.edu
Transmitting editor: R. Geha

During thymic selection ‘mis-selected’ CD8+ T cells exit to the periphery where they are deleted by a Fas/FasL-mediated mechanism, presumably as a result of activation by self-antigens. In the absence of functional FasL, as is the case in autoimmune gld mice, these ‘mis-selected’ T cells develop into unique Thy1+CD4–CD8– TCR{alpha}ß+B220+ lymphocytes [abnormal double negative T (DN T) cells]. Using bioactive FasL-bearing vesicles [FasL vesicle preparation (FasL VP)], we were able to induce acute apoptosis in freshly isolated lymphocytes and to demonstrate that peripheral lymphocytes of gld mice become more sensitive to the FasL-mediated apoptosis as they age. Furthermore, flow cytometric analyses indicated that within this peripheral lymphocyte population, the abnormal DN T cells were preferentially eliminated. The exquisite sensitivity of these abnormal DN T cells is attributed to their increased membrane Fas expression with a concomitant reduction of cytosolic FLIPL. Our data support the hypothesis that specific components of the Fas-mediated apoptotic pathway are modulated in favor of the elimination of auto-reactive T cells as well as those CD8+ T cells that are ‘mis-selected’ in the thymus and escape to the periphery.

Keywords: apoptosis, DN T cells, Fas, FLIP, IL-2, T cell deletion


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