The normal immune system has the capacity to regulate T-cell function, in order to resist the effects of pathogens and yet prevent the development of pathological autoimmune responses. Clonal anergy has been proposed as one potential mechanism for this control of immune reactivity in helper T cells. Anergy is defined as a state of T-cell unresponsiveness that prevents their proliferation in response to antigen stimulation. Previous studies indicated that defective IL-2 production underlies this unresponsiveness, and this arises from a block in signal transduction to the IL-2 gene enhancer. Specifically, it has been shown that: a) transactivation at AP-1 sites fails, b) AP-1 nuclear complex formation is defective, c) c-fos, fosB, and junB expression cannot be induced, d) ERK and JNK activation are blocked, despite normal protein levels, and e) PMA activation of PKC bypasses the clonal anergy defect. Thus, a defect in signal transduction up-stream of MAPK activation at the level of coupling between the TCR/CD3 complex and p21ras appears to be the cause of clonal anergy. With this new information, this research project will target the TCR/p21ras/MAPK/AP-1 signal transduction pathway for further investigation, and define those biochemical alterations that impair the expression of the IL-2 gene.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM054706-03
Application #
2734809
Study Section
Special Emphasis Panel (ZRG2-ALY (01))
Project Start
1996-07-01
Project End
2000-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Agarwal, Pujya; Raghavan, Arvind; Nandiwada, Sarada L et al. (2009) Gene regulation and chromatin remodeling by IL-12 and type I IFN in programming for CD8 T cell effector function and memory. J Immunol 183:1695-704
Zhang, Ruan; Zhang, Na; Mueller, Daniel L (2008) Casitas B-lineage lymphoma b inhibits antigen recognition and slows cell cycle progression at late times during CD4+ T cell clonal expansion. J Immunol 181:5331-9
Mondino, Anna; Mueller, Daniel L (2007) mTOR at the crossroads of T cell proliferation and tolerance. Semin Immunol 19:162-72
Bonnevier, Jody L; Yarke, Cory A; Mueller, Daniel L (2006) Sustained B7/CD28 interactions and resultant phosphatidylinositol 3-kinase activity maintain G1-->S phase transitions at an optimal rate. Eur J Immunol 36:1583-97
Nandiwada, Sarada L; Li, Wei; Zhang, Ruan et al. (2006) p300/Cyclic AMP-responsive element binding-binding protein mediates transcriptional coactivation by the CD28 T cell costimulatory receptor. J Immunol 177:401-13
Vanasek, Tracy L; Nandiwada, Sarada L; Jenkins, Marc K et al. (2006) CD25+Foxp3+ regulatory T cells facilitate CD4+ T cell clonal anergy induction during the recovery from lymphopenia. J Immunol 176:5880-9
Bonnevier, Jody L; Zhang, Ruan; Mueller, Daniel L (2005) E3 ubiquitin ligases and their control of T cell autoreactivity. Arthritis Res Ther 7:233-42
Mueller, Daniel L (2004) E3 ubiquitin ligases as T cell anergy factors. Nat Immunol 5:883-90
Bonnevier, Jody L; Mueller, Daniel L (2002) Cutting edge: B7/CD28 interactions regulate cell cycle progression independent of the strength of TCR signaling. J Immunol 169:6659-63
Li, W; Whaley, C D; Bonnevier, J L et al. (2001) CD28 signaling augments Elk-1-dependent transcription at the c-fos gene during antigen stimulation. J Immunol 167:827-35

Showing the most recent 10 out of 13 publications