Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy

Abstract

T cells with high functional avidity can sense and respond to low levels of cognate Ag, a characteristic that is associated with more potent responses against tumors and many infections, including HIV. Although an important determinant of T cell efficacy, it has proven difficult to selectively induce T cells of high functional avidity through vaccination. Attempts to induce high-avidity T cells by low-dose in vivo vaccination failed because this strategy simply gave no response. Instead, selective induction of high-avidity T cells has required in vitro culturing of specific T cells with low Ag concentrations. In this study, we combined low vaccine Ag doses with a novel potent cationic liposomal adjuvant, cationic adjuvant formulation 09, consisting of dimethyldioctadecylammonium liposomes incorporating two immunomodulators (monomycolyl glycerol analog and polyinosinic-polycytidylic acid) that efficiently induces CD4 Th cells, as well as cross-primes CD8 CTL responses. We show that vaccination with low Ag dose selectively primes CD4 T cells of higher functional avidity, whereas CD8 T cell functional avidity was unrelated to vaccine dose in mice. Importantly, CD4 T cells of higher functional avidity induced by low-dose vaccinations showed higher cytokine release per cell and lower inhibitory receptor expression (PD-1, CTLA-4, and the apoptosis-inducing Fas death receptor) compared with their lower-avidity CD4 counterparts. Notably, increased functional CD4 T cell avidity improved antiviral efficacy of CD8 T cells. These data suggest that potent adjuvants, such as cationic adjuvant formulation 09, render low-dose vaccination a feasible and promising approach for generating high-avidity T cells through vaccination.

A Chlamydia-Specific TCR-Transgenic Mouse Demonstrates Th1 Polyfunctionality with Enhanced Effector Function

“…Thus, triple-positive Th1 Tg cells could be a consequence of improved effector function leading to lower bacterial load (76, 77). In addition, Tg cells may also demonstrate greater functional avidity, which has been linked with improved disease outcomes (78) and expression of decreased levels of inhibitory receptors (79). High avidity T cells are less susceptible to activation-induced cell death (80) and demonstrate increased polyfunctionality (81, 82).…”

High Peptide Dose Vaccination Promotes the Early Selection of Tumor Antigen-Specific CD8 T-Cells of Enhanced Functional Competence

“…Indeed, most attempts to prime high avidity CD8 T-cells by in vivo vaccination have failed, mainly because it remains difficult to induce effective T-cell responses through vaccination with low antigen doses [reviewed in (23)]. Recently, by combining a novel potent adjuvant with low-dose immunization, Billeskov et al (24) found that low antigen dose selectively primed CD4 T-cells of higher functional avidity and protective efficacy in mice. By contrast, CD8 T-cell functional avidity remained unrelated to the vaccine dose (24).…”

“…Recently, by combining a novel potent adjuvant with low-dose immunization, Billeskov et al (24) found that low antigen dose selectively primed CD4 T-cells of higher functional avidity and protective efficacy in mice. By contrast, CD8 T-cell functional avidity remained unrelated to the vaccine dose (24). In cancer patients, we previously reported that vaccination with low peptide dose induced tumor antigenspecific CD8 T-cells of enhanced cytotoxicity (i.e., maximal T-cell responses at saturating antigen concentrations), but there was no difference in their functional avidity (i.e., specific T-cell responses Abbreviations: IFA, incomplete Freund's adjuvant; pMHC, peptide presented by MHC; EM, effector-memory; PD-1, programmed cell death 1; NTAmer, NTA-His tag-containing multimer.…”

Tolerating Factor VIII: Recent Progress

“…This may well reflect lower-avidity peptide binding by these responsive cells, compared to the tetramerpositive cells, which is nevertheless physiologically relevant. Indeed, the respective roles of high-and low-avidity TCR binding interactions are of interest in studies of multiple allo-immune responses including allograft rejection and vaccine efficacy (103)(104)(105). As mentioned earlier, both antibody phenotyping and analysis of secreted cytokines have confirmed the involvement of both Th1 and Th2 subsets of CD4 + T-effectors in inhibitor development.…”