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Biology subjects

Borowska, M. T.

Publications and source records attributed to Borowska, M. T..

2 recordsLinked to original sources

MHC restriction is structurally encoded by the T cell receptor germline

MHC restriction -- the requirement for {beta} T cell receptors (TCRs) to recognize Major Histocompatibility Complex (MHC) molecules when presenting peptide antigens -- is a pillar of adaptive immunity. Here, we provide direct structural evidence for TCR germline-encoded recognition of MHC molecules irrespective of antigenic peptide. We engineered "germline-like" TCRs to eliminate CDR3 specificity for peptide, and a molecular clamping strategy to trap ultra-low-affinity complexes with peptide-MHC for cryo-EM. We find that germline-like TCR/pMHC docking modes are identical to wild-type T cell receptors with intact CDR3 loops, across distinct peptide antigens and MHC alleles. Analysis of human TCR repertoires reveals enrichment of specific V genes and V-V{beta} pairing patterns associated with HLA-A*02 contexts. Thus, the TCR germline encodes the blueprint for MHC restriction, providing a sequence-based framework that could inform computational and AI-driven prediction of TCR specificity.

immunology↗

Biochemical Patterns of Antibody Polyreactivity Revealed Through a Bioinformatics-Based Analysis of CDR Loops

Antibodies are critical components of adaptive immunity, binding with high affinity to pathogenic epitopes. Antibodies undergo rigorous selection to achieve this high affinity, yet some maintain an additional basal level of low affinity, broad reactivity to diverse epitopes, a phenomenon termed "polyreactivity". While polyreactivity has been observed in antibodies isolated from various immunological niches, the biophysical properties that allow for promiscuity in a protein selected for high affinity binding to a single target remain unclear. Using a database of nearly 1,500 polyreactive and non-polyreactive antibody sequences, we created a bioinformatic pipeline to isolate key determinants of polyreactivity. These determinants, which include an increase in inter-loop crosstalk and a propensity for an "inoffensive" binding surface, are sufficient to generate a classifier able to identify polyreactive antibodies with over 75% accuracy. The framework from which this classifier was built is generalizable, and represents a powerful, automated pipeline for future immune repertoire analysis.

immunology↗