# Regulation of CD8+ T cell immunity to tuberculosis

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $704,580

## Abstract

Project Summary. The bacterium Mycobacterium tuberculosis (Mtb) causes more human deaths than any
other pathogen. Mtb elicits strong CD8 T cell responses in people and CD8 T cells make an important
contribution to protection against virulent Mtb in animal models. Human CD8 T cells kill intracellular Mtb, CD8
depletion in non-human primates leads to severe disseminated TB, and recombinant BCG designed to elicit
better CD8 T cell responses is effective in mice and clinical trials have started. CD8 T cells also appear to
enforce latency!in both mice and in people. Despite the vigorous immune response, Mtb evades clearance by
adapting to its host, an idea originally based on its ability to survive in the phagosome and avoid antibody
immunity. We are now learning that Mtb may also avoid T cell immunity. An unexpected finding from the
genomic analysis of Mtb is that the genes encoding T cell epitopes are hyper-conserved, which has been
interpreted to mean that the host T cell response benefits the survival of Mtb, possibly by creating sufficient
inflammation to promote transmission. How does one reconcile T cells as an instrument of TB control, with Mtb
benefiting from T cell responses? Our recent data suggests that not all T cell antigens are alike. We
hypothesize that TB10 is a decoy antigen. We use the term ‘decoy’ to describe its ability to elicit a strong CD8
T cell response that poorly recognizes Mtb-infected macrophages. In the context of immune evasion, decoy
antigens induce T cells that provoke inflammation, but as they fail to recognize infected cells, do not control
Mtb infection. Their immunodominance impairs T cell responses to other antigens, which might be more
efficiently presented by Mtb-infected cells and could be targets of protective immunity. Aim 1 will test the
“decoy” hypothesis, based on the idea that if a decoy antigen is removed, the residual T cell response will be
more effective. We will also will determine the cellular and molecular mechanisms for how Mtb avoids sampling
of it antigens by MHC I. Although Mtb evades CD8 T cell immunity, ultimately, CD8 promote control of Mtb.
The hypothesis of Aim 2 is that a ‘protective’ function of CD4 T cells is to help CD8 T cells differentiate and
express functions that mediate protection against TB. In the absence of CD4 help, we predict that CD8s
become dysfunctional and confer suboptimal protection. Our new preliminary data shows that ‘helped’ CD8 T
cells expand, acquire effector function, and mediate host protection better than ‘helpless’ CD8 T cells. Here we
expect to establish that helped CD8s mediate greater protection than helpless CD8s during primary and
secondary (i.e., memory) responses against Mtb infection. We will define the molecular differences between
helped and helpless CD8 T cells that mediate better protection; and identify the CD4 T cell factors that mediate
help during TB. My lab has developed an innovative and productive research program that seeks to
understand h...

## Key facts

- **NIH application ID:** 9918239
- **Project number:** 5R01AI106725-07
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** SAMUEL M BEHAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $704,580
- **Award type:** 5
- **Project period:** 2013-08-02 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918239

## Citation

> US National Institutes of Health, RePORTER application 9918239, Regulation of CD8+ T cell immunity to tuberculosis (5R01AI106725-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9918239. Licensed CC0.

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