Inhibition of protective immunity against infection by MHC-restricted immunodominance is overcome by vaccination.

Recurrent infections are common, despite robust immune responses. infection elicited protective antibody and T cell responses in mice that expressed the Major Histocompatibility Complex (MHC) of the H-2 haplotype, but not H-2, demonstrating that host genetics drives individual variability. Vaccination with a-toxin or leukotoxin E (LukE) elicited similar antibody and T cell responses in mice expressing H-2 or H-2, but vaccine-elicited responses were inhibited by concomitant infection in H-2-expressing mice. These findings suggested that competitive binding of microbial peptides to host MHC proteins determines the specificity of the immunodominant response, which was confirmed using LukE-derived peptide-MHC tetramers. A vaccine that elicited T cell and antibody responses protected mice that expressed H-2 or H-2, demonstrating that vaccination can overcome MHC-restricted immunodominance. Together, these results define how host genetics determine whether immunity elicted by is protective and provide a mechanistic roadmap for future vaccine design.