# Parenchymal and airway CD4+ T cells in protection against pulmonary tuberculosis

> **NIH VA I01** · LOUIS STOKES CLEVELAND VA MEDICAL CENTER · 2021 · —

## Abstract

Tuberculosis (TB) remains a significant international public health threat, particularly for US military personnel
who are often deployed to areas of high TB prevalence. Mycobacterium tuberculosis (Mtb) is a respiratory
pathogen spread via inhalation of infectious airborne particles. Most infected individuals develop protective
immunity that serves to contain the organism, but approximately 10% will eventually develop active TB.
The localization of mycobacteria-specific CD4+ T cells to the lung appears to be critical to protection against
Mtb infection, and may not be optimized by current TB vaccination with intradermal (ID) M. bovis BCG. Human
studies using lung cells obtainable by bronchoalveolar lavage (BAL) provide a means to assess local immune
responses to Mtb that may be uniquely relevant to evaluating novel TB vaccines. The distinct nature of local
immunity within the lung has been further emphasized by recent murine studies demonstrating that respiratory
infection is followed by the development of CD4+ memory T cells that are localized to the lung parenchyma
and do not rejoin the general circulation. These tissue-resident memory T cells (TRM) display a distinct
phenotype, and also show increased capacity to protect against respiratory infection with Mtb. The use of
intravenous (IV) injection of pan-leukocyte antibodies to identify T cells that are not in communication with the
vasculature has provided a means to sort pulmonary TRM from vascular-associated memory cells. This
intriguing approach has not yet been applied to clarifying the significance of BAL-based studies of immunity to
Mtb; this step is critical, however, to the ultimate application of these insights to human studies.
The overall goal of the current proposal is to clarify the mechanisms by which CD4+ T cells within BAL
differ from and interact with other lung CD4+ T-cell populations to mediate lymphocyte recruitment to
the lung and, ultimately, protection against respiratory challenge with Mtb. Our research team is uniquely
qualified to address these issues, as it includes investigators with experience in bronchoscopy-based studies
of human immunity to Mtb (Richard Silver, PI), murine assessments of immunity to Mtb (W. Henry Boom,
Consultant) and optimization of immune assays involving lung cells from both mice and humans (Tracey
Bonfield, Co-investigator). We will also greatly benefit from the involvement of a pioneer in the application of
TRM methodology to the study of Mtb infection (Daniel Barber of NIAID, Consultant). Our studies will utilize a
murine model of Mtb infection in which lung homogenate cells stained by IV injection (“IV+ T cells”) associated
with the lung vasculature are sorted from T cells that cannot be labeled in this manner. These “IV- T cells”
predominantly display a TRM phenotype and are retained within the parenchyma. We will apply this approach to
evaluate the interactions of IV- and IV+ lung CD4+ T cells and to clarify their relationship to BAL C...

## Key facts

- **NIH application ID:** 9856941
- **Project number:** 5I01CX001283-03
- **Recipient organization:** LOUIS STOKES CLEVELAND VA MEDICAL CENTER
- **Principal Investigator:** RICHARD F SILVER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856941

## Citation

> US National Institutes of Health, RePORTER application 9856941, Parenchymal and airway CD4+ T cells in protection against pulmonary tuberculosis (5I01CX001283-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9856941. Licensed CC0.

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