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

Abstract

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-2b 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-2b 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.

Quantification of heterogeneity in human CD8+T cell responses to vaccine antigens: an HLA-guided perspective

“…[39,38]. More recently, substantial evidence has emerged of the protective role of CD8 + T cell-mediated responses to conserved regions of the genome of HIV-1 [4], Lassa virus [5,40], SARS-CoV-2 [6,7], pandemic influenza [8], and Ebola virus [9]. Yet, we still do not have a single metric to define protective T cell immune responses.…”

“…Most current vaccine strategies aim to confer protection through antibodies (humoral response), which are produced by B cells. Yet, there exists substantial evidence of protective cellular immunity correlated with CD8 + T cell-mediated responses to conserved regions of the genome of HIV-1 [4], Lassa virus [5], SARS-CoV-2 [6,7], pandemic influenza [8], and Ebola virus [9]. Hence, a third challenge is to quantify the potential of CD8 + T cells to induce vaccinemediated immune responses, and if possible, to identify viral immuno-dominant epitopes in these responses.…”

Precision Vaccine Development: Unraveling the Immunoinformatics Code Against Epstein-Barr Virus's T41 Glycoprotein 350/220

“…The creation of the EBV vaccine illustrates the scientific community's tenacity in the face of complex viral obstacles. There is still optimism that an efficient and safe EBV vaccine may be developed, providing a guard against the related disorders, as research and clinical trials move forward (Neto et al, 2023).…”

“…This classification system encompasses over 80% of the HLA-A and HLA-B alleles, aiding in understanding peptide interactions within these genetic variations. Both classes I and II MHC (Major Histocompatibility Complex) molecules serve in presenting Tcell epitopes, which are recognized by distinct subsets of Tcells: CD8 and CD4, respectively, indicating the existence of CD8 and CD4 T-cell epitopes (Neto et al, 2023). Upon encountering their corresponding epitopes, CD8 T-cells transform into cytotoxic T lymphocytes (CTLs), while primed CD4 T-cells differentiate into helper (Th) or regulatory (T-reg) T-cells.…”