Related Experiment Videos
CD2 and CD3 receptor-mediated tolerance: constraints on T cell activation
J D Punch1, J Lin, J Bluestone
1Department of Surgery, University of Michigan, Ann Arbor 48104, USA.
Transplantation
|March 30, 1999
Summary
Inducing antigen-specific allograft tolerance requires specific T cell receptor signaling, not full T cell activation. Anti-CD3epsilon monoclonal antibody (mAb) binding to CD3epsilon is critical for this process, influencing TCRbeta and TCRzeta expression.
Area of Science:
- Immunology
- Transplantation immunology
- T cell signaling
Background:
- Antigen-specific allograft tolerance can be induced in mice using anti-CD2 and anti-CD3epsilon monoclonal antibodies (mAbs).
- Anti-CD2 mAb affects T cell activation pathways influenced by anti-CD3epsilon, prompting investigation into essential components for tolerance induction.
- T cell activation mediated by anti-CD3epsilon relies on Fcgamma receptor (FcgammaR) interactions.
Purpose of the Study:
- To determine the role of FcgammaR-mediated T cell activation in inducing antigen-specific allograft tolerance.
- To identify the specific T cell activation pathways critical for tolerance induction when using anti-CD2 and anti-CD3epsilon mAbs.
Main Methods:
- Comparison of FcgammaR-binding and non-binding anti-CD3epsilon mAbs in conjunction with anti-CD2 for tolerance induction.
- Assessment of FcgammaR-deficient recipients and FcgammaR-blocking mAbs to evaluate FcgammaR involvement.
- Investigation of IL-2 and IL-2 receptor (IL-2R) blocking mAbs to assess IL-2's role.
- Substitution of anti-CD3epsilon with a T cell receptor (TCR) beta subunit-specific mAb to analyze signaling requirements.
Main Results:
- FcgammaR binding was not essential for tolerance induction, as both binding and non-binding anti-CD3epsilon mAbs were equally effective with anti-CD2.
- FcgammaR deficiency or blockade, as well as IL-2 or IL-2R blockade, did not prevent tolerance induction, indicating full T cell activation is unnecessary.
- Replacing anti-CD3epsilon with an anti-TCRbeta mAb abrogated tolerance induction, suggesting a specific signaling requirement.
- Anti-CD3epsilon and anti-TCRbeta mAbs differentially modulated TCR/CD3 complex subunits, with anti-CD3epsilon causing transient TCRbeta and TCRzeta modulation, enhanced by anti-CD2.
Conclusions:
- Full T cell activation is not a prerequisite for inducing allograft tolerance with anti-CD2 plus anti-CD3epsilon mAbs.
- A critical signal transduction pathway involving TCRbeta and TCRzeta expression is essential for tolerance induction.
- Perturbation of this pathway specifically through mAb binding to the CD3epsilon epitope is crucial for successful tolerance induction.