International Immunology Advance Access published online on June 12, 2006
International Immunology, doi:10.1093/intimm/dxl057
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
* To whom correspondence should be addressed. 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.
Received January 31, 2006
Accepted May 9, 2006
Article
Gld mutation of Fas ligand increases the frequency and up-regulates cell survival genes in CD25+CD4+ TR cells
Abdiaziz S. Mohamood 1,
Crystal J. Trujillo 2,
Dongfeng Zheng 1,
Chunfa Jie 3,
Francisco Martinez Murillo 3,
Jonathan P. Schneck 1,
and
Abdel Rahim A. Hamad 1 *
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
Abdel Rahim A. Hamad, E-mail: ahamad{at}jhmi.edu
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E. S. Yolcu, X. Gu, C. Lacelle, H. Zhao, L. Bandura-Morgan, N. Askenasy, and H. Shirwan Induction of Tolerance to Cardiac Allografts Using Donor Splenocytes Engineered to Display on Their Surface an Exogenous Fas Ligand Protein J. Immunol., July 15, 2008; 181(2): 931 - 939. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Reardon, A. Wang, and D. M. McKay Transient Local Depletion of Foxp3+ Regulatory T Cells during Recovery from Colitis via Fas/Fas Ligand-Induced Death J. Immunol., June 15, 2008; 180(12): 8316 - 8326. [Abstract] [Full Text] [PDF]
|
|