A Higher Activation Threshold of Memory CD8+ T Cells Has a Fitness Cost That Is Modified by TCR Affinity during Tuberculosis.

Stephen M Carpenter,Matthew G Booty,Samuel M Behar,Cláudio Nunes-Alves,Sing Sing Way,Padmini Salgame

doi:10.1371/journal.ppat.1005380

Abstract

T cell vaccines against Mycobacterium tuberculosis (Mtb) and other pathogens are based on the principle that memory T cells rapidly generate effector responses upon challenge, leading to pathogen clearance. Despite eliciting a robust memory CD8+ T cell response to the immunodominant Mtb antigen TB10.4 (EsxH), we find the increased frequency of TB10.4-specific CD8+ T cells conferred by vaccination to be short-lived after Mtb challenge. To compare memory and naïve CD8+ T cell function during their response to Mtb, we track their expansions using TB10.4-specific retrogenic CD8+ T cells. We find that the primary (naïve) response outnumbers the secondary (memory) response during Mtb challenge, an effect moderated by increased TCR affinity. To determine whether the expansion of polyclonal memory T cells is restrained following Mtb challenge, we used TCRβ deep sequencing to track TB10.4-specific CD8+ T cells after vaccination and subsequent challenge in intact mice. Successful memory T cells, defined by their clonal expansion after Mtb challenge, express similar CDR3β sequences suggesting TCR selection by antigen. Thus, both TCR-dependent and -independent factors affect the fitness of memory CD8+ responses. The impaired expansion of the majority of memory T cell clonotypes may explain why some TB vaccines have not provided better protection.

Highlights

The goal of T cell vaccination is to establish pre-existing immunity against pathogens in the form of memory T cells
CD8+ T cells are important for enforcing latency of tuberculosis, and for Mycobacterium tuberculosis (Mtb) control in patients with HIV and low CD4 counts
We have some understanding of the fate of memory T cell responses against pathogens that cause chronic infections, such as LCMV clone-13, a model pathogen that causes chronic infection in mice [6,7], little is known about the relative contribution of naïve and memory T cells to the recall response elicited by the human pathogen Mycobacterium tuberculosis (Mtb)

Summary

Introduction

The goal of T cell vaccination is to establish pre-existing immunity against pathogens in the form of memory T cells. Two features of memory T cells make them superior to naïve T cells in mediating protection. Memory T cells have undergone a cycle of expansion and contraction, leading to a greater frequency of pathogen-specific T cells than present among the naïve T cell repertoire. We have some understanding of the fate of memory T cell responses against pathogens that cause chronic infections, such as LCMV clone-13, a model pathogen that causes chronic infection in mice [6,7], little is known about the relative contribution of naïve and memory T cells (and the resulting 1° and 2° responses, respectively) to the recall response elicited by the human pathogen Mycobacterium tuberculosis (Mtb)

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Conclusion