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.