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Low 2-dimensional CD4 T cell receptor affinity for myelin sets in motion delayed response kinetics
Kristen M Rosenthal1, Lindsay J Edwards, Joseph J Sabatino
1Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, United States of America.
Plos One
|March 14, 2012
Summary
T cells with low antigen affinity, like those targeting self-peptides in autoimmune disease, can still achieve full activation, albeit delayed. This suggests a mechanism for how these T cells contribute to autoimmune conditions.
Area of Science:
- Immunology
- T cell biology
- Autoimmunity
Background:
- T cell recognition of self-peptides can lead to autoimmune disease, while responses to pathogens require effective immunity.
- Mechanisms of central and peripheral tolerance may influence the affinity of T cells for self-antigens versus foreign antigens.
Purpose of the Study:
- To investigate the differences in T cell receptor (TCR) affinity between self-reactive and pathogen-specific T cells.
- To explore how varying TCR affinities impact T cell activation kinetics and signaling pathways.
Main Methods:
- Utilized T cell receptor (TCR) transgenic mice expressing self-reactive (2D2) and viral-specific (SMARTA) T cells.
- Compared the 2D affinity of T cells for their cognate ligands.
- Analyzed T cell activation markers, cytokine production, and intracellular signaling pathways (e.g., phosphorylation of p38, Erk, Jun) following antigen stimulation.
Main Results:
- Viral-specific T cells (SMARTA) exhibited >10,000-fold higher 2D affinity compared to self-reactive T cells (2D2).
- Despite lower affinity, 2D2 T cells showed delayed but complete activation (proliferation, cytokine production).
- SMARTA cells displayed rapid signaling and activation kinetics, while 2D2 cells showed delayed signaling and activation, which could be restored with a higher affinity antigen.
Conclusions:
- T cell receptor (TCR) affinity significantly influences T cell activation kinetics.
- Time can compensate for low TCR affinity, enabling full T cell activation.
- Low-affinity T cells, potentially involved in autoimmunity, may achieve full activation through prolonged stimulation.
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