# Focusing the vaccine-elicited T cell response on the recognition of Mtb-infected cells

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $209,375

## Abstract

Abstract. The HIV epidemic, the increasing prevalence of diabetes in China and India, and the spread of drug-
resistant Mycobacterium tuberculosis (Mtb) are perpetuating the global tuberculosis (TB) epidemic. While BCG
is widely used as a vaccine, it efficacy in preventing pulmonary TB is limited. Therefore, TB vaccine
development continues to be an important priority. Several vaccine candidates are being evaluated clinically,
but since their ability to prevent TB must be tested empirically, progress is slow and expensive. While there is
general agreement that T cells mediate immunity to Mtb, there is little ability to predict which antigens are
targets of protective immune responses. For a vaccine to be effective, the elicited antigen-specific T cells must
recognize infected cells. However, there may be an important difference between the repertoire of antigens
presented by DC in the LN during T cell priming occurs, and the antigens that are presented by infected
macrophages in the lung. Such differences in antigen processing arise for many reasons: 1) the DC that prime
T cells are not always infected but have acquired nonviable Mtb antigens; 2) DC and macrophages present
antigen differently; 3) inflammatory signals alter antigen presentation (e.g., IFNγ) in the lung. Whether an
infected cell presents bacterial epitopes at a sufficient density for T cell recognition may depend on the
number, location, and metabolic activity of intracellular bacteria, which can alter bacterial antigen production.
Finally, the idea that Mtb evades detection of the immune response is well-documented and the mechanisms
are being elucidated. In a limited number studies, immunodominant T cell responses fail to recognize infected
cells. One way to think about this phenomenon is that uninfected APC acquire and present Mtb proteins, which
both elicits and perpetuates T cell responses to abundant antigens; however, these antigens are inefficiently
presented by Mtb-infected cells. We propose to develop a vaccine that preferentially stimulates T cells that
recognize Mtb infected cells. As part of this proposal, we will develop an assay to quantify vaccine-elicited T
cells that recognize Mtb infected cells, which we envision as being essential for pre-clinical and clinical
vaccine development. By vaccinating mice with macrophages or DC that have been infected in vitro with the
18b auxotroph of Mtb, we will test whether we can skew the immune response toward antigens that are
presented by Mtb-infected macrophages. This will allow us to test the concept that a vaccine that
elicits T cells that recognizes Mtb-infected cells will have greater efficacy in protecting the host. If
successful, identification of which antigens are targets of protective immunity would greatly accelerate vaccine
development. Our overarching model is that antigen presentation by uninfected DC determines the hierarchy
of Mtb-specific T cells elicited during infection. However, the relative abundance of M...

## Key facts

- **NIH application ID:** 9816615
- **Project number:** 5R21AI136922-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** SAMUEL M BEHAR
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $209,375
- **Award type:** 5
- **Project period:** 2018-11-02 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9816615

## Citation

> US National Institutes of Health, RePORTER application 9816615, Focusing the vaccine-elicited T cell response on the recognition of Mtb-infected cells (5R21AI136922-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9816615. Licensed CC0.

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