# Mechanistic investigation of differential T cell responses to distinct Mycobacterium tuberculosis antigens

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $45,498

## Abstract

Abstract
Tuberculosis (TB) is a major global health threat and the only licensed TB vaccine, Bacille Calmette-Guérin
(BCG), is inadequate: despite widespread use of BCG, there were 9.9 million new TB cases globally in 2020.
Thus, improved vaccines against Mtb are urgently needed. T cell responses remain the primary goal of TB
vaccines, as CD4 T cells are necessary to control Mtb in humans and animal models. T cell vaccines have been
thus far unsuccessful in preventing infection, but the recent clinical trial of M72-AS01E demonstrated ~50%
efficacy as a Prevention of Disease (POD) vaccine. Since TB is transmitted by those with active disease, which
is characterized by inflammation and immunopathology, a vaccine that reduces or prevents active disease and
immunopathology can have a large impact on the global problem of TB. However, the most optimal antigen
target(s) for TB vaccines are not defined, and the lack of evolutionary variation in the known antigens of Mtb
suggests that T cell recognition of those antigens is not detrimental to the pathogen or beneficial to the host.
Through a comprehensive analysis of genomes from 216 phylogenetically diverse Mtb, my advisor and his
colleagues discovered a distinct subset of Mtb antigens that are sequence variable and exhibit evidence of
evolutionary selection pressure. In a screen of DNA vaccines encoding these sequence variable antigens, I
discovered one (encoding 4 sequence variable antigens) that alters immunopathology and inflammatory Th1
responses in mice subsequently challenged with Mtb, without reducing lung bacterial burdens. Additional studies
in our laboratory have demonstrated distinct CD4 T cell effector responses to these same antigens in humans.
From these and other results, we hypothesize that a functionally distinct T cell response to one or more of our
vaccine antigens is responsible for altered immunopathology in vaccinated mice after challenge. The objective
of this proposal is to characterize the cellular responses in vaccinated mice after challenge and identify the
mechanism that accounts for altered immunopathology. I will characterize the cellular response using spectral
flow cytometry and immunofluorescence microscopy. I will then characterize the vaccine-specific T cell response
using peptide:MHC tetramers and single cell RNA sequencing to identify potential mechanisms mediating the
altered immunopathology response. Finally, I will identify the underlying mechanism(s) by performing adoptive
transfers of sorted T cells to identify the phenotype of the T cells that alter immunopathology during infection.
This work will identify differential T cell responses to distinct Mtb antigens and demonstrate a role of
immunoregulation in mediating a vaccine response to Mtb infection. The findings will provide an understanding
of T cell responses to Mtb antigens that can modulate immunopathology. This will provide a framework of
vaccine-induced immunoregulatory responses to inform development ...

## Key facts

- **NIH application ID:** 10867404
- **Project number:** 5F31AI172360-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Zachary Howard
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $45,498
- **Award type:** 5
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867404

## Citation

> US National Institutes of Health, RePORTER application 10867404, Mechanistic investigation of differential T cell responses to distinct Mycobacterium tuberculosis antigens (5F31AI172360-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10867404. Licensed CC0.

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