Murine CD8 T-cell functional avidity is stable in vivo but not in vitro: Independence from homologous prime/boost time interval and antigen density.

Connie B Gilfillan,Grégory Verdeil,Chensu Wang,Mathilde Allard,Darrell J Irvine,Martin F Bachmann,Daniel E Speiser,Michael Hebeisen,Nathalie Rufer,Mona O Mohsen

doi:10.1002/eji.201948355

Abstract

It is known that for achieving high affinity antibody responses, vaccines must be optimized for antigen dose/density, and the prime/boost interval should be at least 4 weeks. Similar knowledge is lacking for generating high avidity T‐cell responses. The functional avidity (FA) of T cells, describing responsiveness to peptide, is associated with the quality of effector function and the protective capacity in vivo. Despite its importance, the FA is rarely determined in T‐cell vaccination studies. We addressed the question whether different time intervals for short‐term homologous vaccinations impact the FA of CD8 T‐cell responses. Four‐week instead of 2‐week intervals between priming and boosting with potent subunit vaccines in C57BL/6 mice did not improve FA. Equally, similar FA was observed after vaccination with virus‐like particles displaying low versus high antigen densities. Interestingly, FA was stable in vivo but not in vitro, depending on the antigen dose and the time interval since T‐cell activation, as observed in murine monoclonal T cells. Our findings suggest dynamic in vivo modulation for equal FA. We conclude that low antigen density vaccines or a minimal 4‐week prime/boost interval are not crucial for the T‐cell's FA, in contrast to antibody responses.

Highlights

It has long been known that B-cell responses employ affinity maturation to optimize antibody affinity over time [1, 2]
It was of interest to determine whether the functional avidity (FA) of CD8 T cells would be improved after a 4-week delay compared to 2-week, as a minimal 4-week interval is standard clinical practice for vaccinations inducing antibody responses
In contrast to what is known for B-cell response-inducing vaccines, these results indicate that delaying the second vaccination from 2 to 4 weeks does not improve the FA of the peptide-specific T-cell response

Summary

Introduction

It has long been known that B-cell responses employ affinity maturation to optimize antibody affinity over time [1, 2]. Other studies demonstrated FA changes over time, in part due to shifts in the clonal dominance and in the TCR usage [10, 11]. Even though TCR affinity and T cells’ FA are important correlates of protection from disease [4, 12], it remains poorly understood whether certain vaccine doses, formulations, or P/B schemes induce T-cell responses with better affinity and FA. Many studies investigating changes in the FA of the peptide-specific CD8 T-cell response have focused on altered peptide ligands to artificially modulate the TCR pool recruited. Changing epitopes from prime to boost and/or effector phase preclude direct conclusions on eventual avidity maturation because avidity differences may be due to fine specificity differences

Methods

Results

Conclusion