# Direct activation of TGFbeta by an Mtb virulence factor to suppress CD4 T-cell responses

> **NIH NIH R21** · SEATTLE CHILDREN'S HOSPITAL · 2021 · $282,750

## Abstract

PROJECT SUMMARY
Mycobacterium tuberculosis (Mtb) promotes its survival by secreting a range of virulence factors that modulate
immunity. As a result, protective immunity to tuberculosis (TB) is exceedingly difficult to achieve, whether by
vaccination or natural infection. One clear correlate of protection from TB is an effective CD4 T cell response
that leads to production of interferon gamma (IFN. However, a long-standing question is why even a robust
IFN response fails to effectively control Mtb at the site of infection in the lung. Recent work has shown that the
lung, and in particular the granuloma, is an immunosuppressive environment and that the most protective Mtb-
specific T cells are systematically excluded from these sites where they are needed the most. While the
mechanisms for this spatial exclusion are not fully understood, the immunosuppressive cytokine transforming
growth factor  (TGF is emerging as a potent factor of T cell subversion in TB. TGF strongly co-localizes
with Mtb in the granuloma, suggesting that Mtb may directly activate TGF to subvert this microenvironment,
disable CD4 T cell function, and extinguish IFN signaling. We now show that Mtb lysate and culture filtrate
protein can indeed effectively activate TGF from its inert latent precursor. This activity is heat-labile, secreted
by Mtb, and is inhibited by serine hydrolase inhibitors. Here, we will test the hypothesis that Mtb secretes a
serine protease virulence factor that directly processes and activates TGF to suppress productive CD4 T cell
activation at the site of Mtb infection. This project aims to identify a new and direct host-pathgen interaction
and a mechanism of Mtb pathogenesis that underlies the immune system’s failure to control Mtb infection.

## Key facts

- **NIH application ID:** 10191677
- **Project number:** 1R21AI159389-01
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Christoph Grundner
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $282,750
- **Award type:** 1
- **Project period:** 2021-03-20 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10191677

## Citation

> US National Institutes of Health, RePORTER application 10191677, Direct activation of TGFbeta by an Mtb virulence factor to suppress CD4 T-cell responses (1R21AI159389-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10191677. Licensed CC0.

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