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Development of T cells expressing an altered TCR complex.
Wen-Hui Lee1, Thomas Ramos, Ludmila Krymskaya
1Division of Immunology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
European Journal of Immunology
|September 30, 2003
Summary
Alternative T cell receptors (TCRs) using the FcRgamma chain, instead of the typical zeta homodimer, impact T cell development. These alternative TCRs lead to reduced CD4+ T cell numbers and impaired signaling, suggesting a role for signaling strength in T cell immunity.
Area of Science:
- Immunology
- T cell biology
- Molecular signaling
Background:
- Normal T cells utilize conventional T cell receptor (TCR) complexes, typically featuring a zeta homodimer.
- Alternative TCR complexes can incorporate the FcRgamma chain, potentially influencing T cell function and development.
- The precise role of these alternative TCRs and their associated signaling molecules in T cell development remains largely uncharacterized.
Purpose of the Study:
- To investigate the impact of alternative TCR complexes containing the FcRgamma chain on T cell development and function.
- To determine the signaling requirements for T cell development in the presence of FcRgamma-containing TCRs.
- To elucidate the mechanism behind altered T cell development associated with alternative TCR complexes.
Main Methods:
- Generation of FcRgamma transgene-expressing, zeta chain-deficient (FcRgammaTG, zetaKO) mice.
- Introduction of a DO11.10 TCR (DOTCR) transgene into FcRgammaTG, zetaKO mice for specific T cell tracking.
- Analysis of T cell populations (CD4+ thymocytes), calcium (Ca2+) flux, and proliferative responses upon stimulation.
- Assessment of T cell development across different MHC backgrounds.
Main Results:
- FcRgammaTG, zetaKO mice exhibited reduced percentages and numbers of CD4+ T cells compared to wild-type controls.
- The development of CD4+, DOTCR+ thymocytes was altered in FcRgammaTG, zetaKO mice, influenced by MHC background.
- T cell development in these mice required zeta-associated protein (ZAP)-70 and lck kinases.
- T cells expressing alternative TCR complexes showed impaired Ca2+ flux and proliferative responses.
Conclusions:
- Altered CD4+ T cell development in FcRgammaTG, zetaKO mice is likely due to reduced signaling strength, not qualitative signal differences.
- The FcRgamma chain, with its single immunoreceptor tyrosine-based activation motif (ITAM), contributes to weaker signaling compared to the zeta homodimer's multiple ITAMs.
- These findings highlight the importance of TCR signaling strength in regulating T cell development and potentially immune responses.