GSBS Dissertations and Theses

Publication Date

2016-06-30

Document Type

Doctoral Dissertation

Academic Program

Millennium PhD

Department

Microbiology and Physiological Systems

First Thesis Advisor

Samuel M. Behar, PhD

Keywords

Tuberculosis, Mycobacterium tuberculosis, CD8-Positive T-Lymphocytes, T-Lymphocytes, Vaccination, Vaccines

Subjects

Dissertations, UMMS; Tuberculosis; Mycobacterium tuberculosis; CD8-Positive T-Lymphocytes; T-Lymphocytes; Vaccination; Vaccines

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 TCRb 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 CDR3b 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.

DOI

10.13028/M2T59Q

Rights and Permissions

Copyright is held by the author, with all rights reserved.

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