Stephen Carpenter, MD, PhD

We currently have no reliable vaccine to prevent tuberculosis (TB), a disease that kills 1.5 million people worldwide every year. Immune cells called CD4 T cells are critical for protection against active TB. A subset of these cells called macrophages respond to cells in the lungs called macrophages that become infected after inhalation of Mycobacterium tuberculosis (Mtb), the bacteria that causes TB. A critical unmet need for TB vaccine development is to learn more about T cells that can recognize Mtb-infected macrophages. By applying cutting-edge single-cell analyses, we will track and compare Mtb-reactive memory CD4 T cells among individuals who have not developed TB despite heavy exposure. Memory T cells are long-lived immune cells capable of recognizing foreign particles they were previously exposed to. Results from this project will contribute to TB vaccine development efforts by defining benchmark signature features of protective memory CD4 T cells linked to prevention of active TB.  

Update:
In the first award period, we developed an approach to identify and track individual memory CD4 T cells that become activated in response to Mtb-infected macrophages. We also developed a system to compare memory T cells circulating in the blood to those residing in the lungs from the same individuals. The ability to study both blood and lung CD4 T cells from the same donor allows us to ask which aspects of T cell responses derived from blood trigger immune responses to Mtb in the lungs. These findings will enable the discovery of candidate antigens and benchmarks of T cell function which will inform TB vaccine development.

Final Project Update: 
We have no reliable vaccine to prevent tuberculosis (TB), a disease that kills 1.5 million people every year. CD4 T cells are critical for protection against active TB and are a focus of vaccine development efforts since they can directly target macrophages infected with Mycobacterium tuberculosis (Mtb) as well as recruit other immune cells. However, we discovered that not all Mtb-specific CD4 T cells recognize macrophages that become infected with Mtb. In our work, we sought to determine which CD4 T cell functions, and antigen specificities, are linked to prevention of tuberculosis.  

To accomplish this goal, we studied memory CD4 T cells from people with latent Mtb infection (LTBI), identifying a subset that became activated in response to Mtb-infected macrophages. By analyzing their T cell receptors (TCRs), we identified groups of CD4 T cells with TCRs likely to target Mtb antigens. This approach allowed us to focus on the Mtb-specific memory CD4 T cells from both the blood and lungs of individuals with LTBI and to assess the commonalities between Mtb-specific T cells in the lungs vs. peripheral blood. We will continue to expand this study to include more lung samples as well as individuals with varying risks of developing active TB to pinpoint protective T cell functions and antigens linked to protection. The results from this project will contribute to TB vaccine development by determining the functions, TCRs, and antigen-specificities of protective memory CD4 T cells.