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OX40-mediated memory T cell generation is TNF receptor-associated factor 2 dependent.
Rodney A Prell1, Dean E Evans, Colin Thalhofer
1Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR 97213, USA.
Journal of Immunology (Baltimore, Md. : 1950)
|November 25, 2003
Summary
Tumor necrosis factor receptor-associated factor 2 (TRAF2) is crucial for generating Ag-specific memory T cells via OX40 signaling. TRAF2 deficiency impairs T cell function and survival, highlighting its role in immune memory.
Area of Science:
- Immunology
- Molecular Biology
- Cellular Signaling
Background:
- Tumor necrosis factor receptor-associated factor 2 (TRAF2) is an adapter protein involved in signal transduction.
- OX40 is a receptor that plays a role in T cell activation and memory formation.
Purpose of the Study:
- To investigate the in vivo role of TRAF2 in OX40-mediated generation of Ag-specific memory T cells.
- To elucidate the mechanism by which TRAF2 influences T cell expansion and effector function.
Main Methods:
- Generation of OVA-specific TCR transgenic mice crossed with TRAF2 dominant-negative (TRAF2 DN) mice.
- In vivo antigen stimulation and OX40 engagement.
- Assessment of long-lived T cell numbers and effector T cell function.
- Analysis of CTLA-4 expression and effect of CTLA-4 blockade.
Main Results:
- TRAF2 DN T cells showed dramatically reduced numbers of long-lived OVA-specific T cells and impaired effector function compared to wild-type T cells after Ag stimulation and OX40 engagement.
- OX40 engagement led to the down-regulation of CTLA-4 in vivo.
- CTLA-4 blockade partially rescued the defect in TRAF2 DN T cells, suggesting a role for CTLA-4 in the TRAF2-mediated OX40 signaling pathway.
Conclusions:
- TRAF2 is essential for OX40-mediated memory T cell expansion and survival.
- Down-regulation of CTLA-4 by OX40 signaling is a potential mechanism to enhance early T cell expansion, with TRAF2 playing a key role in this process.