Determining Protective Features of Human Memory T-cells to Inform Mycobacterium tuberculosis Vaccine Development

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Project Summary / Abstract Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (Mtb), is a disease that kills 1.4 million people every year. There is no reliable vaccine to prevent TB, yet many latently-infected individuals are protected from progressing to active TB despite heavy Mtb exposure living in an endemic setting. CD4+ T cells are critical for host protection against TB as they interact directly with Mtb-infected cells, secrete cytokines and cytolytic molecules, and recruit or augment other immune cells. However, the candidate and others find that not all T cells specific for Mtb antigens are able to recognize Mtb-infected macrophages, the niche cell for Mtb. A critical unmet need for vaccine development is to define the antigen specificities and functions of T cells that can recognize infected macrophages and prevent progression to active TB. In Aim 1, the candidate uses autologous ex vivo co-culture and T cell antigen receptor (TCR) sequencing to determine the proportion, antigen specificities and functions of memory CD4+ T cells that recognize Mtb-infected macrophages. In Aim 2, the candidate expands on this system to compare the repertoires of memory CD4 T cells that respond to infected macrophages among two groups of individuals who live in a setting endemic for TB yet differ in their susceptibility to active disease. Using single-cell transcriptomics, the candidate compares the functions and TCR repertoires of Mtb- specific memory CD4+ T cells isolated from exposed individuals who do not develop active TB (“stable” latent Mtb infection) vs. individuals who will later progress to active TB (“pre-TB” progressors). Results from this project will define key features of protective memory CD4+ T cells that are linked to the prevention of active TB, providing benchmarks for vaccine development and improvement of TB risk stratification. This 5-year K08 program provides mentoring, training in human immunology, translational research and single-cell transcriptomics for Dr. Stephen Carpenter, a T cell immunologist and infectious disease physician at Case Western Reserve University (CWRU). The institutional environment at CWRU combines an established TB research unit, BSL-3 flow cytometry, cell sorting, single-cell RNA sequencing, and expertise in bioinformatics together with a premier graduate program for scientific interaction and courses. The longstanding Uganda- CWRU Research Collaboration for TB enables clinical and translational work in a TB endemic setting. The candidate is establishing a lab with the long-term goals of understanding the defining features of protective memory T cell responses to Mtb. He has recruited mentors with substantial expertise in translational TB research, T cell biology and single-cell transcriptomics, including Drs. Henry Boom and Mark Cameron at CWRU, and Dr. Sam Behar (UMass Medical School). Completion of this K08 project will transition the candidate into an independent investigator, positioning his research program to use powerful single-cell immune profiling approaches to track and study antigen-specific human memory T cells.