TCRs with high affinity for foreign pMHC show self-reactivity

Area of Science:

• Immunology
• T cell biology
• Molecular immunology

Background:

• T cells utilize T cell receptors (TCRs) to recognize foreign peptide-major histocompatibility complexes (pMHCs).
• High-affinity TCRs are typically eliminated through negative selection, a process that prevents autoimmunity.
• The mechanisms driving negative selection of high-affinity TCRs against foreign antigens remain incompletely understood.

Purpose of the Study:

• To investigate the molecular basis for negative selection of high-affinity TCRs.
• To understand how TCR affinity influences T cell repertoire selection.
• To explore the implications of TCR flexibility and affinity for immune responses.

Main Methods:

• Utilized in vitro yeast display technology to isolate high-affinity TCRs from the 2C T cell clone.
• Characterized the biophysical properties of isolated TCRs, including on-rates and cross-reactivity.
• Employed T cell hybridoma assays to assess the stimulatory capacity of high-affinity TCRs by self-pMHC.

Main Results:

• Isolated high-affinity TCRs exhibited fast on-rates and reduced complementarity determining region (CDR) flexibility.
• These high-affinity TCRs demonstrated cross-reactivity with various cognate pMHCs.
• T cell hybridomas expressing high-affinity TCRs were activated by endogenous self-pMHC, indicating a propensity for negative selection.

Conclusions:

• The immune system appears to prioritize a repertoire of flexible, low-affinity TCRs.
• This selection process may occur at the expense of high-affinity TCRs that could offer more effective antigen recognition.
• Reduced TCR flexibility and cross-reactivity contribute to the negative selection of high-affinity TCRs, even against foreign antigens.