Immunoregulatory T cells (Treg cells) have recently been identified as an active mechanism of immune suppression for maintaining T cell tolerance. Among several sets of Treg cells described, CD4+CD25+ Treg cells comprise 5-10% of peripheral CD4+ T cells. These cells, identified in mice and humans, exhibit potent immunoregulatory functions and are considered """"""""professional regulatory T cells"""""""". In mouse models, transfer of CD4+CD25+ Treg cells can suppress autoimmune diseases. Treg cells have also been implicated in the regulation of anti-tumor immunity, graft-versus-host disease (GVHD) associated with transplantation, and anti-microbial immunity. Thus, the survival or death of CD4+CD25+ Treg cells is likely to be important for immune homeostasis. The mechanisms that govern CD4+CD25+ Treg cell survival remains elusive, although the generation of CD4+CD25+ Treg cells is CD28-dependent. In preliminary studies, several Bcl-x isoforms were identified including a novel Bcl-x isoform, Bcl-x-gamma, which is characterized by a unique C-terminus and inhibits T cell apoptosis after TCR ligation. These results, as well as the reports of others, further showed that CD28 co-stimulatory signals can up-regulate the expression of the anti-apoptotic proteins Bcl-xL and Bcl-x-gamma, suggesting that Bcl-xgamma and Bcl-xL promote T cell survival after CD3/CD28 co-ligation. This proposal will test the hypothesis that CD4+CD25+ Treg cells have a specific survival program in which Bcl-x genes play an important role through CD28. The corollary hypothesis is that a shift toward survival, rather than apoptosis, in CD4+CD25+ Treg cells may lead to reduced autoimmunity, decreased GVHD, and diminished, deleterious tissue damage associated with anti-microbial immunity. The primary goal of this proposal is to define the survival program of CD4+CD25+ Treg cells, and especially the roles of Bcl-x gene family members. This goal will be pursued through the following specific aims: (1) To determine the function of Bcl-x proteins in CD4+CD25+ Treg cells by analysis of the expression and pro-survival function of these genes in the Treg cells; (2) To determine whether Bcl-x up-regulation is responsible for the anergic state of CD4+CD25+ Treg cells; and (3) To determine the potential for CD4+CD25+ Treg cells, rescued from death by transfection with Bcl-x-gamma and Bcl-xL, to reduce the immunopathology in a mouse model of autoimmune gastritis. Molecular definition of the survival program of CD4+CD25+ Treg cells may lead to development of novel therapeutic strategies for autoimmune diseases, as well as viral and bacterial infections by specifically promoting Treg cell survival.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI054514-05
Application #
7075404
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Prograis, Lawrence J
Project Start
2003-06-01
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
5
Fiscal Year
2006
Total Cost
$122,040
Indirect Cost
Name
Temple University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Xiong, Zeyu; Yan, Yan; Song, Jian et al. (2009) Expression of TCTP antisense in CD25(high) regulatory T cells aggravates cuff-injured vascular inflammation. Atherosclerosis 203:401-8
Xiong, Zeyu; Song, Jian; Yan, Yan et al. (2008) Higher expression of Bax in regulatory T cells increases vascular inflammation. Front Biosci 13:7143-55
Yang, Xiao-Feng; Yin, Ying; Wang, Hong (2008) VASCULAR INFLAMMATION AND ATHEROGENESIS ARE ACTIVATED VIA RECEPTORS FOR PAMPs AND SUPPRESSED BY REGULATORY T CELLS. Drug Discov Today Ther Strateg 5:125-142
Yan, Y; Xiong, Z; Zhang, S et al. (2008) CD25high T cells with a prolonged survival inhibit development of diabetes. Int J Immunopathol Pharmacol 21:767-80
Yan, Y; Chen, Y; Yang, F et al. (2007) HLA-A2.1-restricted T cells react to SEREX-defined tumor antigen CML66L and are suppressed by CD4+CD25+ regulatory T cells. Int J Immunopathol Pharmacol 20:75-89
Xiong, Z; Liu, E; Yan, Y et al. (2007) A novel unconventional antigen MPD5 elicits anti-tumor humoral immune responses in a subset of patients with polycythemia vera. Int J Immunopathol Pharmacol 20:373-80
Xiong, Zeyu; Yan, Yan; Liu, Enli et al. (2007) Novel tumor antigens elicit anti-tumor humoral immune reactions in a subset of patients with polycythemia vera. Clin Immunol 122:279-87
Xiong, Z; Shaibani, A; Li, Y-P et al. (2006) Alternative splicing factor ASF/SF2 is down regulated in inflamed muscle. J Clin Pathol 59:855-61
Xiong, Zeyu; Liu, Enli; Yan, Yan et al. (2006) An unconventional antigen translated by a novel internal ribosome entry site elicits antitumor humoral immune reactions. J Immunol 177:4907-16
Yang, Fan; Chen, Irene H; Xiong, Zeyu et al. (2006) Model of stimulation-responsive splicing and strategies in identification of immunogenic isoforms of tumor antigens and autoantigens. Clin Immunol 121:121-33

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