Updated project metadata. Major Histocompatibility Complex of Class II (MHCII) antigen presentation is a key event of adaptive immunity. HLA-DM favors the presentation of kinetically stable peptide-MHCII complexes but does not bind peptides itself and exhibits only a low degree of polymorphism. To date, no evidence for altered function of DM due to natural variations has been reported. We define the presence of DM haplotypes in human populations covered by the 1000 Genomes Project and probe their activity in antigen presentation assays. Our results indicate a clear linkage between DMA*0103 and DMB*0107 never reported before. Thehe corresponding heterodimer features a distinct activity profile when compared to the most frequent allotype (DMA*0101-DMB*0101). In vitro experiments demonstrate a broader pH activity profile for the new allotype, explaining its characteristic cellular function. Together, our results suggest that natural variations of DM have important consequences for an individual’s adaptive immune response.