# Mechanisms of IFNg-independent T cell and B cell-mediated protection in TB.

> **NIH NIH R01** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $800,200

## Abstract

In humans, exposure to Mycobacterium tuberculosis (Mtb) results in varied infection and disease outcomes. 5-
10% of individuals infected with Mtb manifest disease, with evidence of infection in the remaining majority
evinced only as positivity of IGRA (interferon gamma release assay). Given that the risk of developing
reactivation TB is ~10% per lifetime in immunocompetent LTBI, it is thought the anti-TB immunity developed in
this population can control the infection rather effectively. Another group, termed resisters, are defined as
persons who remain IGRA-negative despite prolonged heavy exposure to Mtb. Resisters, compared to LTBI
subjects, exhibit an interferon (IFN)γ-independent T cell response. The non-IFNγ T cell response to Mtb antigens
(Ags), in conjunction with class switch recombination and the relatively high binding affinity Abs developed in
resisters, suggests that this population has been infected with and has established an adaptive immune response
to Mtb. Our Brazil household contact (HHCs) study of pulmonary TB showed differential IGRA response in the
exposed HHCs despite having similar exposure to the infectious index case. Approximately 45% of HHCs were
found to be IGRA negative. We defined the resister IGRA negative group as “Resistant to IGRA Conversion”
(RIC) and the IGRA positive group as IGRA Converters (IC). Our preliminary data show that IFNγ-independent
adaptive T cell immunity is engaged in RIC-HHCs and peripheral blood mononuclear cells from RIC-HHCs
restrict Mtb growth. Further, preliminary data points to GM-CSF-secreting T cells as a likely component of the
IFNγ-independent T cell response. GM-CSF signaling enhances IL-1β production and given that IL-1β is critical
to anti-bacterial immunity in TB, we hypothesize that stable GM-CSF secreting memory T cells contribute to the
RIC phenotype and the cytokine may also have a significant role in IC-HHCs. Accumulating evidence suggests
that antibodies (Abs) play a role in regulating infection and disease outcomes in individuals exposed to Mtb,
including the RIC- and IC-HHCs. We showed that Tfh cells (the CD4 T helper cell that is essential for the
development of the B cell and Ab responses) from LTBI subjects harbor phenotypically distinct subsets that have
been linked to discrepant B cell-regulatory functions in varied immunological systems. We thus posit that varied
functions of Tfh cells in individuals exposed to Mtb may influence infection outcome by directing the development
of distinct Ab responses. Comparative characterization of anti-TB immunity in RIC-HHCs versus IC-HHCs is a
major goal of this proposal. The proposed studies will likely illuminate the IFNγ-independent T cell mediated
immunological mechanisms that define the RIC phenotype, and of protective mechanisms mediated by the Tfh
cell-B cell-Ab axis--this may lead to the development of novel vaccine targets. We will reconsent HHCs, retest
them for their IGRA status and then recruit to the study the ones wh...

## Key facts

- **NIH application ID:** 10882693
- **Project number:** 1R01AI177853-01A1
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** John R. Chan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $800,200
- **Award type:** 1
- **Project period:** 2024-08-26 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882693

## Citation

> US National Institutes of Health, RePORTER application 10882693, Mechanisms of IFNg-independent T cell and B cell-mediated protection in TB. (1R01AI177853-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10882693. Licensed CC0.

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