# Overcoming restrained lung trafficking by memory CD4+ T cells to prevent active tuberculosis in people living with HIV

> **NIH NIH R21** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $281,750

## Abstract

PROJECT SUMMARY / ABSTRACT
 Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (Mtb), is a disease that kills 1.5
million people every year, and there is no reliable vaccine to prevent TB. CD4 T cells are critical for host
protection, acting through direct interaction with Mtb-infected cells via multiple effector mechanisms. People
living with HIV (PWH) who harbor latent Mtb infection (LTBI) have up to 20-fold greater risk of developing active
disease. The elevated risk of active TB in PWH persists despite maintaining CD4 T cell counts over 500 / uL and
effective viral suppression. However, an exact mechanism for the increased risk of TB among PWH with stable
CD4 counts is unclear. Given the efforts on T cell vaccines for TB, a key research priority is to determine which
specific attributes of memory CD4 T cells are critical to lowering the risk of TB in PWH. Identification of the unique
features of T cells from protected hosts would accelerate vaccine development and identify targets for host-
directed therapy. Recently, Mtb-specific CD4 T cells that express fractalkine receptor (CX3CR1) were shown to
contain potent effector functions, including robust IFNg secretion and cytolytic function, yet they are considered
non-protective since they are retained in lung microvasculature and are largely absent from lung parenchyma in
the mouse and non-human primate (NHP) models of TB. Interestingly, CX3CR1+ T cells are found with increased
frequency in PWH, possibly due to chronic inflammation. Our overarching hypothesis is that despite maintaining
stable total CD4 counts, the inflammatory state associated with HIV infection increases the proportion of
CX3CR1+ CD4 T cells specific for Mtb, among other effects, and impairs their lung parenchymal trafficking. This
project seeks to understand the trafficking and adhesion receptor expression and function of Mtb-specific
memory CD4 T cells, comparing those from HIV+ and HIV- individuals with LTBI. In Aim 1, we will use an
autologous ex vivo co-culture system to identify the memory CD4 T cells able to respond to Mtb-infected
macrophages and determine which trafficking and adhesion receptors they express. We further evaluate the
heterogeneity in T cell effector function and T cell antigen receptor (TCR) repertoire among the Mtb-specific CD4
T cells from HIV+ and HIV- individuals. In Aim 2, we will utilize a novel T cell migration assay to determine which
surface receptors are associated with the trafficking of memory CD4 T cells through vascular endothelium toward
Mtb-infected macrophages. For a vaccine to effectively prevent TB, it must elicit T cells that are able to mobilize
to the site of infection in the lung and recognize infected cells. Results from this study will determine the
differences in function and trafficking receptor expression between Mtb-specific CD4 T cells isolated from HIV-
and HIV+ individuals with LTBI, and the extent to which these differences correlate with T cell tra...

## Key facts

- **NIH application ID:** 10546668
- **Project number:** 1R21AI167675-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Stephen Matthew Carpenter
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $281,750
- **Award type:** 1
- **Project period:** 2022-08-05 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10546668

## Citation

> US National Institutes of Health, RePORTER application 10546668, Overcoming restrained lung trafficking by memory CD4+ T cells to prevent active tuberculosis in people living with HIV (1R21AI167675-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10546668. Licensed CC0.

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