GSBS Dissertations and Theses

ORCID ID

0000-0002-2234-2306

Publication Date

2018-03-15

Document Type

Doctoral Dissertation

Academic Program

MD/PhD

Department

Microbiology and Physiological Systems

First Thesis Advisor

Samuel Behar, MD, PhD.

Keywords

tuberculosis, T cells, antigen recognition, infectious diseases, immunology, immune evasion, decoy antigen

Abstract

Mycobacterium tuberculosis (Mtb) causes human tuberculosis, and more people die of it than of any other pathogen in the world. Immunodominant antigens elicit the large majority of T cells during an infection, making them logical vaccine candidates. Yet, it is still unknown whether these immunodominant antigen-specific T cells recognize Mtb-infected cells. Two immunodominant antigens, TB10.4 and Ag85b, have been incorporated into vaccine strategies. Surprisingly, mice vaccinated with TB10.4 generate TB10.4-specific memory CD8+ T cells but do not lead to additional protection compared to unvaccinated mice during TB. Ag85b-specific CD4+ T cells are also generated during vaccination, but the literature on whether these cells recognize Mtb-infected cells is also inconsistent.

We demonstrate that TB10.4-specific CD8+ T cells do not recognize Mtb-infected cells. However, under the same conditions, Ag85b-specific CD4+ T cells recognize Mtb-infected macrophages and inhibit bacterial growth. In contrast, polyclonal CD4+ and CD8+ T cells from the lungs of infected mice can specifically recognize Mtb-infected macrophages, suggesting macrophages present antigens other than the immunodominant TB10.4. The antigen location may also be critical for presentation to CD8+ T cells, and live Mtb may inhibit antigen presentation of TB10.4. Finally, we propose that TB10.4 is a decoy antigen as it elicits a robust CD8+ T cell response that poorly recognizes Mtb-infected macrophages, allowing Mtb to evade host immunity.

DOI

10.13028/M27M3N

Rights and Permissions

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

Available for download on Thursday, November 01, 2018

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