International Immunology Advance Access originally published online on June 12, 2006
International Immunology 2006 18(8):1265-1277; doi:10.1093/intimm/dxl057
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Gld mutation of Fas ligand increases the frequency and up-regulates cell survival genes in CD25+CD4+ TR cells
1 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2 Department of Chemistry/Biochemistry, St Mary's University, San Antonio, TX 78228, USA
3 Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Correspondence to: A. Hamad; E-mail: ahamad{at}jhmi.edu
The Fas pathway and regulatory T (TR) cells play intertwining roles in controlling T cell tolerance through deletion and suppression of autoreactive T cells. Impairment of either mechanism causes severe T cell lymphoproliferation albeit with opposing outcomes. T cell lymphoproliferation induced by defective Fas pathway does not cause overt lymphocytic infiltration but rather prevents an important set of T cell-mediated autoimmune diseases. In contrast, deficiency in TR cell causes fulminant autoimmunity in very early life and fatal lymphocytic infiltration. These observations suggest existence of unidirectional fail/safe mechanism that compensate for defects in the Fas pathway but not in regulatory cells. To gain insights into how animals compensate for defects in the Fas system, we analyzed the impact of generalized lymphoproliferative disease (gld) mutation on survival, function and transcription profile of CD25+CD4+ TR cells. Our results show that all CD4 T cells expanded in gld mice. However, CD25+CD4+ TR cells are disproportionately increased in the pool of CD4 T cells perhaps due to their unique apoptosis phenotype. Freshly isolated CD25+CD4+ TR cells, unlike CD25–CD4+ T cells, are highly sensitive to FasL-induced apoptosis in the steady state. CD25+CD4+ TR cells that accumulate in gld mice express similar level of Foxp3, and have suppression potency and TR gene expression profile as wild-type CD25+CD4+ TR cells. Furthermore, the transcription profile of gld CD25+CD4+ TR cells is characterized by differential expression of genes involved in cell survival, metabolism and innate immune responses. These results provide a strong cellular and molecular basis for understanding why impaired Fas pathway prevents an important subset of T cell-mediated autoimmune diseases.
Keywords: Fas pathway, gld mutation, T cell, tolerance/suppression
Transmitting editor: S. Nagata
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