T cell allorecognition via molecular mimicry

Area of Science:

• Immunology
• Molecular Biology
• Structural Biology

Background:

• T cells play a crucial role in adaptive immunity by recognizing peptide-MHC complexes.
• Alloreactivity, where T cells react against foreign tissues, is a major hurdle in transplantation.
• Human leukocyte antigens (HLA) exhibit extensive polymorphism, contributing to immune responses.

Purpose of the Study:

• To investigate the mechanism of T cell alloreactivity mediated by the LC13 T cell receptor (TCR).
• To explore the role of molecular mimicry in T cell recognition of disparate peptide-HLA (pHLA) complexes.
• To elucidate the structural basis of TCR engagement with allogeneic pHLA complexes.

Main Methods:

• T cell receptor (TCR) selection and characterization.
• Structural analysis of peptide-HLA (pHLA) complexes.
• Investigation of T cell alloreactivity against various HLA allotypes and peptides.

Main Results:

• The LC13 TCR, initially selected for self-HLA-B*0801, alloreacted with specific B44 allotypes (HLA-B*4402, HLA-B*4405) presenting different peptides.
• Identical engagement of disparate pHLA complexes by the LC13 TCR, accommodating allopeptide mimicry.
• An induced-fit mechanism was observed where peptides adopted similar conformations post-TCR ligation.
• Alloreactivity was dependent on HLA and peptide sequence, with a single residue polymorphism in HLA-B*4403 abrogating the response.

Conclusions:

• Molecular mimicry, dependent on specific HLA and peptide interactions, is a significant mechanism underlying T cell alloreactivity.
• TCR specificity dictates the extent of molecular mimicry and subsequent alloreaction.
• Understanding HLA and peptide-dependent molecular mimicry is crucial for managing T cell responses in transplantation and autoimmune diseases.