Correlative CD4 and CD8 T-cell immunodominance in humans and mice: Implications for preclinical testing

Antigen-specific T-cell recognition is restricted by Major Histocompatibility Complex (MHC) molecules, and differences between CD4 and CD8 immunogenicity in humans and animal species used in preclinical vaccine testing are yet to be fully understood. In this study, we addressed this matter by analyzing experimentally identified epitopes based on published data curated in the Immune Epitopes DataBase (IEDB) database. We first analyzed SARS-CoV-2 spike (S) and nucleoprotein (N), which are two common targets of the immune response and well studied in both human and mouse systems. We observed a weak but statistically significant correlation between human and H-2^b mouse T-cell responses (CD8 S specific (r = 0.206, p = 1.37 × 10^-13); CD4 S specific (r = 0.118, p = 2.63 × 10^-5) and N specific (r = 0.179, p = 2.55 × 10^-4)). Due to intrinsic differences in MHC molecules across species, we also investigated the association between the immunodominance of common Human Leukocyte Antigen (HLA) alleles for which HLA transgenic mice are available, namely, A*02:01, B*07:02, DRB1*01:01, and DRB1*04:01, and found higher significant correlations for both CD8 and CD4 (maximum r = 0.702, p = 1.36 × 10^-31 and r = 0.594, p = 3.04^-122, respectively). Our results further indicated that some regions are commonly immunogenic between humans and mice (either H-2^b or HLA transgenic) but that others are human specific. Finally, we noted a significant correlation between CD8 and CD4 S- (r = 0.258, p = 7.33 × 10²¹) and N-specific (r = 0.369, p = 2.43 × 10¹⁴) responses, suggesting that discrete protein subregions can be simultaneously recognized by T cells. These findings were confirmed in other viral systems, providing general guidance for the use of murine models to test T-cell immunogenicity of viral antigens destined for human use.