HLA-II peptide-binding diversity shapes humoral immune responses and susceptibility to infections

Infectious diseases represent a leading cause of mortality worldwide and have shaped the evolution of the human immune system. Human leukocyte antigen (HLA) class II molecules are key to the humoral immune response by presenting peptides to helper T cells. The peptide-binding range varies greatly among HLA-II variants, but the role of this variation in humoral immunity and infection susceptibility has remained unexplored. Here, we integrate data on HLA-II immunopeptidomics and antibody responses in ~1500 individuals and demonstrate that a broad peptide-binding repertoire of HLA-II is linked to antibody production against specific pathogen-associated proteins and more favorable outcomes in several common infections. In the UK Biobank, individuals carrying such HLA-II molecules had a reduced risk of severe infections and up to a 45% lower incidence of diseases caused by common pathogens. These findings suggest that the peptide diversity presented by HLA-II variants shapes humoral immunity and can serve as a risk factor for infection susceptibility. Human leukocyte antigen class II (HLA-II) are involved in the presentation of peptides to helper T cells which guide in the B cell response and antibody production. Here Magyari et al, show that HLA-II peptide binding diversity impacts the humoral immune response and susceptibility to infection. T.V., M.M. and A.Z. are partners of the Horizon Health consortium “ID-DarkMatter-NCD” (project number [PN]: 101136582) and gratefully acknowledge support from the EU. Views and opinions expressed are however those of the authors only and do not neces... [2126 chars]