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

点击翻译按钮获取中文摘要

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 trafficking through vascular endothelium. These results will provide benchmarks for TB vaccine development and will reveal targets for receptor blockade that could improve T cell trafficking toward Mtb-infected cells.