COMBO‐RATE: An Experimentally Validated Bioinformatic Tool to Identify Promiscuous HLA Restrictions
- 1Center for Vaccine Innovation, La Jolla Institute for Immunology (LJI) La Jolla California USA
- 2Fiocruz Ceará Eusébio Brazil
- 3Department of Medicine, Division of Infectious Diseases and Global Public Health University of California, San Diego (UCSD) La Jolla California USA
Abstract
Defining HLA restriction of T cell epitopes is essential for understanding immune responses in infectious disease, autoimmunity and vaccine design. Current bioinformatic programmes, including the IEDB RATE tool, enable inference of single‐HLA restrictions from immune response data of HLA‐typed donors. However, T cell epitopes are frequently presented by multiple HLA alleles, a phenomenon termed promiscuous restriction, limiting the utility of single‐allele approaches. To address this limitation, we developed COMBO‐RATE, an extension of RATE that systematically evaluates combinations of HLA alleles to identify multi‐allelic restriction patterns. Analysis of three independent datasets spanning distinct antigen systems and different epitope discovery strategies revealed that promiscuous restriction is a near‐universal feature of immunodominant epitopes. Focusing on the 43 immunodominant CD4+ T cell epitopes identified in a B. pertussis genome‐wide screen, COMBO‐RATE outperformed conventional RATE, identifying restrictions for 35 of 43 epitopes, compared to 24 by RATE alone, and uncovered 64 additional allele restrictions, including 29 unique alleles. Experimental validation using single‐HLA transfected cell lines and antigen presentation assays confirmed COMBO‐RATE‐inferred restrictions, demonstrating that a single epitope can be independently presented by distinct HLA alleles. Overall, COMBO‐RATE provides a robust and scalable framework for defining complete HLA restriction profiles from existing population response data, with important implications for the design of vaccines requiring broad HLA coverage across genetically diverse populations. This pipeline is available as both a Python package and a user‐friendly web application.
Related
- AptViralDB: A repository of experimentally validated antiviral aptamers
- EVLncRNAs 4.0: an updated database of experimentally validated functional long non-coding RNAs with evidence-grounded AI access
- An experimentally validated manually curated genome-scale metabolic model of Enterococcus faecium TX0016 reproduces high-throughput phenotyping data
- Direct Bioconjugations of Diverse Payloads using an Extraordinarily Donor-Promiscuous Flavin Transferase
- Promiscuous ATP-Dependent Diazotases Discovered by Comprehensive Genome Mining Based on Sequence Similarity Network Analysis.
BibTeX
@article{nevarezmejia2026comborate,
title = {{COMBO‐RATE: An Experimentally Validated Bioinformatic Tool to Identify Promiscuous HLA Restrictions}},
author = {Jessica Nevarez‐Mejia and Raphael Trevizani and Adam Abawi and Kendall Kearns and Emil Johansson and Aaron Sutherland and Alba Grifoni and Ricardo da Silva Antunes and Alessandro Sette},
journal = {HLA},
year = {2026},
month = oct,
doi = {10.1111/tan.71060},
url = {https://europepmc.org/article/PMC/PMC13722996},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - COMBO‐RATE: An Experimentally Validated Bioinformatic Tool to Identify Promiscuous HLA Restrictions
AU - Jessica Nevarez‐Mejia
AU - Raphael Trevizani
AU - Adam Abawi
AU - Kendall Kearns
AU - Emil Johansson
AU - Aaron Sutherland
AU - Alba Grifoni
AU - Ricardo da Silva Antunes
AU - Alessandro Sette
PY - 2026
DA - 2026/10/31
JO - HLA
DO - 10.1111/tan.71060
UR - https://europepmc.org/article/PMC/PMC13722996
AB - Defining HLA restriction of T cell epitopes is essential for understanding immune responses in infectious disease, autoimmunity and vaccine design. Current bioinformatic programmes, including the IEDB RATE tool, enable inference of single‐HLA restrictions from immune response data of HLA‐typed donors. However, T cell epitopes are frequently presented by multiple HLA alleles, a phenomenon termed promiscuous restriction, limiting the utility of single‐allele approaches. To address this limitation, we developed COMBO‐RATE, an extension of RATE that systematically evaluates combinations of HLA alleles to identify multi‐allelic restriction patterns. Analysis of three independent datasets spanning distinct antigen systems and different epitope discovery strategies revealed that promiscuous restriction is a near‐universal feature of immunodominant epitopes. Focusing on the 43 immunodominant CD4+ T cell epitopes identified in a B. pertussis genome‐wide screen, COMBO‐RATE outperformed conventional RATE, identifying restrictions for 35 of 43 epitopes, compared to 24 by RATE alone, and uncovered 64 additional allele restrictions, including 29 unique alleles. Experimental validation using single‐HLA transfected cell lines and antigen presentation assays confirmed COMBO‐RATE‐inferred restrictions, demonstrating that a single epitope can be independently presented by distinct HLA alleles. Overall, COMBO‐RATE provides a robust and scalable framework for defining complete HLA restriction profiles from existing population response data, with important implications for the design of vaccines requiring broad HLA coverage across genetically diverse populations. This pipeline is available as both a Python package and a user‐friendly web application.
SN - 2059-2302
SN - 2059-2310
ER -