Why does the same infection cause only mild symptoms in one person, but more serious disease in another? A new study led by the Systems Immunology Research Group, together with several international collaborators, suggests that part of the answer lies in how broadly the immune system can present fragments of pathogens to its own immune cells.
Defense against infections does not begin with the immune system attacking the pathogen. The immune system has to first recognize what it is facing. At the center of this recognition process are HLA class II molecules. These molecules present small protein fragments, called peptides, to immune cells. This step is essential for activating helper T cells, which in turn support B cells in producing targeted antibodies.
However, not all HLA-II molecules present the same range of peptides. These molecules have exceptional genetic variability. Consequently, it is likely that two individuals carry different variants. Some variants can bind and present a broad diversity of pathogen-derived peptides, while others are more selective. This property is known as HLA-II peptide-binding promiscuity, or more simply, peptide-binding diversity.
In the new study, we asked whether this diversity influences antibody responses and susceptibility to infections. To answer this question, we combined several large-scale datasets. First, we mapped how broadly different HLA-II variants can present peptides. We analyzed antibody responses in approximately 1,500 individuals and used genetic and health-record data from hundreds of thousands of participants in the UK Biobank to examine whether HLA-II peptide-binding diversity is linked to infection risk.
The results pointed in the same direction. Individuals carrying HLA-II molecules with broader peptide-binding repertoires were more likely to show antibody responses. This association was specific to disease-causing microbes and was not observed for non-pathogenic microbes, suggesting that broader HLA-II presentation may support more effective humoral immunity to infections.
The clinical data further supported this link. In the UK Biobank, individuals with higher HLA-II peptide-binding diversity had a lower risk of severe infections requiring hospital care. Moreover, these individuals were less likely to have experienced various infections during their lifetime. High HLA-II peptide-binding diversity decreased the risk for several infection groups, including HPV-related diseases, viral skin warts, herpes zoster, skin and soft tissue infections, lower respiratory tract infections, and fungal infections. The strongest association was found for genital warts linked to HPV.
However, the picture was not simply “broader is always better.” High peptide-binding diversity may provide protection against common infections encountered throughout life. At the same time, lower HLA-II peptide-binding diversity was associated with a lower risk for HIV infection, indicating that fastidious HLA-II variants may help against certain less common or antigenically unusual pathogens.
Notably, HLA-II peptide-binding diversity is not only affecting infection risk, but responses to influenza vaccination. Higher HLA-II peptide-binding diversity was associated with stronger antibody responses in individuals aged 60–79, but not in younger adults or those over 80. This suggests that there may be an age window in which broader HLA-II presentation can particularly support vaccine-induced antibody responses.
The findings suggest that HLA-II peptide-binding diversity could become a useful biomarker for understanding infection susceptibility and vaccine responsiveness. Personalized infection prevention and vaccine design is still a long-term, but realistic goal.
The study was conducted within the framework of the ID-DarkMatter-ICD consortium, funded by the European Union’s Horizon Europe research and innovation programme under Grant Agreement No. 101136582 and by the Swiss State Secretariat for Education, Research and Innovation (SERI). Partners at the Medical University of Vienna and the University Medical Center Groningen contributed extensive datasets on individual antibody profiles and participated in the data analysis.
