TY - JOUR
T1 - Gld mutation of Fas ligand increases the frequency and up-regulates cell survival genes in CD25+CD4+ TR cells
AU - Mohamood, Abdiaziz S.
AU - Trujillo, Crystal J.
AU - Zheng, Dongfeng
AU - Jie, Chunfa
AU - Murillo, Francisco Martinez
AU - Schneck, Jonathan P.
AU - Hamad, Abdel Rahim A.
N1 - Funding Information:
The authors thank Themos Dassopoulos, Mark Soloski, William Baldwin III, Nagaraju Kanneboyina, Joan Bieler and Malarvizhi Durai for critical reading of the manuscript and Pamela Talalay for editing the manuscript. This work was supported by National Institutes of Health grants DK069279 and DK066039 (A.R.A.H.)
PY - 2006/8
Y1 - 2006/8
N2 - The Fas pathway and regulatory T (T R) 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.
AB - The Fas pathway and regulatory T (T R) 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.
KW - Fas pathway
KW - Gld mutation
KW - T cell
KW - Tolerance/suppression
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U2 - 10.1093/intimm/dxl057
DO - 10.1093/intimm/dxl057
M3 - Article
C2 - 16769751
AN - SCOPUS:33748452820
SN - 0953-8178
VL - 18
SP - 1265
EP - 1277
JO - International Immunology
JF - International Immunology
IS - 8
ER -