A Donor T-Cell Receptor Structural Signature Determines Alloreactive Potential and Predicts Acute Graft-Versus-Host...

Area of Science:

• Immunology
• Transplantation Science
• Computational Biology

Background:

• Acute graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation.
• Current donor selection methods do not consider T-cell receptor (TCR) structural diversity, a key factor in immune response.

Purpose of the Study:

• To investigate the structural basis of human alloreactivity in the context of GVHD.
• To develop a predictive model for acute GVHD risk based on TCR architecture.

Main Methods:

• Characterization of over 64,000 alloreactive T-cell receptor (TCR) clonotypes.
• Analysis of TCR structural features including CDR3β length, biophysical properties, and VJ gene usage.
• Development and validation of the R50 metric for quantifying clonal dominance.

Main Results:

• Human alloreactivity is governed by a predictable structural signature in TCRs.
• Pathogenic T cells show specific TCR structural alterations and shared public clonotypes.
• The R50 metric independently predicted a six-fold increased risk of acute GVHD.

Conclusions:

• TCR structural modeling offers a novel approach for pre-transplant risk stratification.
• The R50 metric provides a precise, assay-independent measure of GVHD risk.
• This computational platform can enhance donor selection and improve transplant outcomes.