Alloreactive T cells respond specifically to multiple distinct peptide-MHC complexes.

Area of Science:

• Immunology
• Molecular Biology
• T cell biology

Background:

• The specificity of alloreactive T cells for peptide-major histocompatibility complex (pMHC) ligands is not fully understood.
• Alloreactive T cells are crucial in transplantation immunology and autoimmune diseases.

Purpose of the Study:

• To investigate the molecular basis of alloreactive T cell specificity.
• To determine if alloreactive T cells recognize single or multiple ligands.

Main Methods:

• Screening of 60 I-E(k)-alloreactive T cells against 83 naturally processed peptides.
• Analysis of T cell recognition patterns and interaction interfaces with pMHC ligands.

Main Results:

• Identified 9 T cells reactive to naturally processed peptides.
• Three T cells demonstrated polyspecificity, recognizing multiple, non-homologous peptides.
• These polyspecific T cells utilized distinct I-E(k) contact residues for each peptide interaction, indicating specific recognition.

Conclusions:

• Alloreactive T cells possess a germline-encoded capacity for polyspecificity, recognizing diverse ligands.
• This polyspecificity, rather than degeneracy, explains the high frequency of alloreactive T cells.
• Findings provide critical insights into the fundamental nature of T cell receptor specificity.