The CMV-Specific CD8+ T Cell Response Is Dominated by Supra-Public Clonotypes with High Generation Probabilities.

Kilian Schober,Michael Flossdorf,Monika Hammel,Pim Fuchs,Lorenzo Fanchi,Jonas Mir,Dirk H Busch

doi:10.3390/pathogens9080650

Abstract

Evolutionary processes govern the selection of T cell clonotypes that are optimally suited to mediate efficient antigen-specific immune responses against pathogens and tumors. While the theoretical diversity of T cell receptor (TCR) sequences is vast, the antigen-specific TCR repertoire is restricted by its peptide epitope and the presenting major histocompatibility complex (pMHC). It remains unclear how many TCR sequences are recruited into an antigen-specific T cell response, both within and across different organisms, and which factors shape both of these distributions. Infection of mice with ovalbumin-expressing cytomegalovirus (IE2-OVA-mCMV) represents a well-studied model system to investigate T cell responses given their size and longevity. Here we investigated > 180,000 H2kb/SIINFEKL-recognizing TCR CDR3α or CDR3β sequences from 25 individual mice spanning seven different time points during acute infection and memory inflation. In-depth repertoire analysis revealed that from a pool of highly diverse, but overall limited sequences, T cell responses were dominated by public clonotypes, partly with unexpectedly extreme degrees of sharedness between individual mice (“supra-public clonotypes”). Public clonotypes were found exclusively in a fraction of TCRs with a high generation probability. Generation probability and degree of sharedness select for highly functional TCRs, possibly mediated through elevating intraindividual precursor frequencies of clonotypes.

Highlights

T cells play a crucial role in the control of chronic and latent infections
While we have previously focused our analysis on the successive outgrowth of dominating clones [29], in this work we first investigated how many new unique clones are recruited during the course of the immune response
This revealed that the T cell receptor (TCR) repertoire stabilizes during memory inflation in terms of its evenness, and in terms of its composition of unique clonotypes

Summary

Introduction

T cells play a crucial role in the control of chronic and latent infections. Latent infection with CMV affects 60–100% of the general population [1]—largely depending on the socioeconomic status—but does not cause any symptoms unless the immune system is compromised. For example hematopoietic stem cell transplantation recipients, CMV is a major cause of morbidity and mortality [2]. The significance of T cell mediated protection from overt CMV infection is further strongly supported by adoptive transfer experiments in mice [3,4] and through the success of adoptive T cell therapy in human patients [5,6]. Viral latency and immune control seem to be in equilibrium. Inflationary T cells often harbor a senescent phenotype [9]

Methods

Results

Conclusion