Project 2

"Human T cell responses permissive for progression to active TB disease"

Program Director: Joel Ernst, MD

An important characteristic of tuberculosis is that the pathogen can persist in a clinically- and bacteriologically silent form, termed latent TB infection (LTBI). Although individuals with LTBI possess M. tuberculosis (Mtb) antigen-specific T cell responses, in some, these are qualitatively or quantitatively insufficient, and LTBI progresses to active, transmissible, TB disease. Numerous studies provide evidence for a host-protective role of T cells in TB, but differences in the T cell responses that mediate stable LTBI and T cell responses that allow progression to active TB have not yet been identified. Similarly, the role of T cell responses in preventing future episodes of TB in the setting of re-exposure has not been prospectively studied nor quantified. A major reason for the limited understanding of T cell responses that prevent or allow progression is the lack of data on Mtb-specific T cell responses in persons with LTBI prior to their progression to active TB. Although multiple differences have been identified in T cell responses between individuals with LTBI and those with active TB, they do not provide insight into the T cell responses that are adequate or inadequate for preventing progression to active disease. Therefore, in Project 2 we will study T cell antigen recognition, phenotypes, and functional responses in a prospective study of high-risk subjects. These studies will provide samples prior to the development of active TB, and will allow unique comparisons of T cell responses in those that remain healthy and those that progress to active TB (Aims 1 & 2).

A potential difference between T cells that mediate stable LTBI and those that allow progression to active TB is in the antigens or epitopes that they recognize. One possibility is that, as in hepatitis C or HIV, T cell responses that are directed at a greater number or broader range of epitopes are more likely to control Mtb. A second possibility, especially for a pathogen with ~4,000 orfs and complex mechanisms for regulating its gene expression in vivo, is that the precise antigens or epitopes recognized by T cells are important determinants of the outcome of infection with Mtb. A third possibility is that expansion, differentiation and effector responses among antigen-specific T cells dictates whether an individual remains healthy or progresses to active TB; this possibility is not exclusive of the others.

Another factor confounding our understanding of the progression from LTBI to active TB disease is the impact of repeated exposures to active TB cases, which is increasingly relevant in high TB incidence settings. The traditional construct regarding risk of progression to active TB diseaseña 5% risk of progression in the first two years following infectionñand an additional 5% risk over the remaining lifetime does not consider the impact of repeated exposures. Historical studies suggest that prior LTBI may provide as much as a 70% risk reduction in progression to active TB disease. However, more recent studies highlight the role of re-exposure and reinfection, sufficient to neutralize the benefit of preventive therapy for LTBI. Given the risk of repeated exposures in high TB burden settings, we will perform an epidemiologic study to prospectively examine the clinical and immunologic impact of repeated exposures to Mtb among individuals with LTBI (Aim 3).

The goal of Project 2 is to understand why some individuals with LTBI progress to active TB disease while others do not. In Aims 1 & 2, we will identify T cell responses that distinguish stable control of LTBI and those associated with progression to active TB. In Aim 3, we will better understand the potential protective effects of prior LTBI with repeated exposure. Together, the data from Project 2 will provide important insights for vaccine development, while enhancing public health strategies for addressing the global TB epidemic. The results will also link closely to those generated in Project 1 and Project 3.