Inhibition of protective immunity against <i>Staphylococcus aureus</i> infection by MHC-restricted immunodominance is overcome by vaccination.

Abstract

Recurrent <i>Staphylococcus aureus</i> infections are common, despite robust immune responses. <i>S. aureus</i> infection elicited protective antibody and T cell responses in mice that expressed the Major Histocompatibility Complex (MHC) of the H-2^d haplotype, but not H-2^b, 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^d or H-2^b, but vaccine-elicited responses were inhibited by concomitant infection in H-2^d-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^d or H-2^b, demonstrating that vaccination can overcome MHC-restricted immunodominance. Together, these results define how host genetics determine whether immunity elicted by <i>S. aureus</i> is protective and provide a mechanistic roadmap for future vaccine design.