Epitope Specificity Delimits the Functional Capabilities of Vaccine-Induced CD8 T Cell Populations

Abstract

Despite progress toward understanding the correlates of protective T cell immunity in HIV infection, the optimal approach to Ag delivery by vaccination remains uncertain. We characterized two immunodominant CD8 T cell populations generated in response to immunization of BALB/c mice with a replication-deficient adenovirus serotype 5 vector expressing the HIV-derived Gag and Pol proteins at equivalent levels. The Gag-AI9/H-2Kd epitope elicited high-avidity CD8 T cell populations with architecturally diverse clonotypic repertoires that displayed potent lytic activity in vivo. In contrast, the Pol-LI9/H-2Dd epitope elicited motif-constrained CD8 T cell repertoires that displayed lower levels of physical avidity and lytic activity despite equivalent measures of overall clonality. Although low-dose vaccination enhanced the functional profiles of both epitope-specific CD8 T cell populations, greater polyfunctionality was apparent within the Pol-LI9/H-2Dd specificity. Higher proportions of central memory-like cells were present after low-dose vaccination and at later time points. However, there were no noteworthy phenotypic differences between epitope-specific CD8 T cell populations across vaccine doses or time points. Collectively, these data indicate that the functional and phenotypic properties of vaccine-induced CD8 T cell populations are sensitive to dose manipulation, yet constrained by epitope specificity in a clonotype-dependent manner.

The Mutation-Associated Neoantigen Functional Expansion of Specific T Cells (MANAFEST) Assay: A Sensitive Platform for Monitoring Antitumor Immunity

“…TCRseq of these pMHC + T cells demonstrated dominance of Vβ 28-01 within this antigen-specific population (Fig. 2B, Supplementary Table S3), which is consistent with prior findings that different T-cell clonotypes specific for the same antigen often utilize the same Vβ gene segment (34–38). In comparison to 92.5% of T cells utilizing Vβ 28-01 in pMHC + T cells, only 7.0% of pMHC − CD8 + T cells used this gene segment (Supplementary Table S4).…”

Safety and immunogenicity of the therapeutic vaccine TG1050 in chronic hepatitis B patients: a phase 1b placebo-controlled trial

“…Interestingly, it has been published in various pre-clinical studies that an intermediate dose of Ad5based vaccines is typically associated with better quality of T-cells (higher polyfunctionality, strongest proliferative capacity and lower expression of exhaustion markers) compared with higher doses. [26][27][28] Unfortunately, we could not perform additional immune assays such as recently reported in the field (e.g., tetramer analysis, ex vivo ELISPOT, phenotypic analysis 25,[29][30][31] in order to better characterize the detected cells due to limited sample quantities. Such analyses will need to be conducted in future clinical trials.…”

Transient IL-10 receptor blockade can enhance CD8+T cell responses to a simian adenovirus-vectored HIV-1 conserved region immunogen

“…We identified 2 candidate overlapping peptides, 42 and 43, which were retested individually. Peptide 42, comprising Pol residues 126-140, contains a previously-defined mouse 14,17 and human CD8 C T cell epitope. IL-10R blockade enhanced IFN-g production and in vivo cytotoxicity in response to peptide 42 at 21 days, although only the latter was statistically significant (Fig.…”