Age and CMV-Infection Jointly Affect the EBV-Specific CD8+ T-Cell Repertoire.

Josien Lanfermeijer,Martijn Vos,Marion Hendriks,José A M Borghans,Peter C De Greef,Josine Van Beek,Debbie Van Baarle

doi:10.3389/fragi.2021.665637

Abstract

CD8+ T cells play an important role in protection against viral infections. With age, changes in the T-cell pool occur, leading to diminished responses against both new and recurring infections in older adults. This is thought to be due to a decrease in both T-cell numbers and T-cell receptor (TCR) diversity. Latent infection with cytomegalovirus (CMV) is assumed to contribute to this age-associated decline of the immune system. The observation that the level of TCR diversity in the total memory T-cell pool stays relatively stable during aging is remarkable in light of the constant input of new antigen-specific memory T cells. What happens with the diversity of the individual antigen-specific T-cell repertoires in the memory pool remains largely unknown. Here we studied the effect of aging on the phenotype and repertoire diversity of CMV-specific and Epstein-Barr virus (EBV)-specific CD8+ T cells, as well as the separate effects of aging and CMV-infection on the EBV-specific T-cell repertoire. Antigen-specific T cells against both persistent viruses showed an age-related increase in the expression of markers associated with a more differentiated phenotype, including KLRG-1, an increase in the fraction of terminally differentiated T cells, and a decrease in the diversity of the T-cell repertoire. Not only age, but also CMV infection was associated with a decreased diversity of the EBV-specific T-cell repertoire. This suggests that both CMV infection and age can impact the T-cell repertoire against other antigens.

Highlights

CD8+ T cells play an important role in the control and clearance of viral infections
We focused on CMVA2−NLV-specific and EBVA2−GLC-specific T cells, as these antigen-specific T cells are readily detectable in the T-cell pool at all ages
We show that CMV infection is associated with a lower diversity of the EBVA2−GLC-specific T-cell repertoire

Summary

Introduction

CD8+ T cells play an important role in the control and clearance of viral infections. One of the key components of a protective T-cell response is the recognition of viral epitopes via the T-cell receptor (TCR). T-cell receptors are formed via the random process of somatic V(D)J-recombination, leading to a large collection of TCRs with different specificities (Market and Papavasiliou, 2003). It is generally assumed that the diversity of the T-cell receptor repertoire is positively correlated with the level of protection against infectious diseases (Turner et al, 2009). Together with less efficient priming of T cells (Briceno et al, 2016), this may explain why both CD8+

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