Functional Definition of T Cell Receptors Associated with Protection from Pulmonary TB Infection and Disease - Modified Project Summary/Abstract Section Exacerbated by HIV, tuberculosis (TB) remains a leading cause of infectious disease mortality worldwide. TB cannot be reasonably eliminated in the absence of a vaccine. While CD4 and CD8 T cells and their associated proinflammatory and cytolytic capacity have been associated with protection in various animal models, correlates of protective immunity in humans remain enigmatic. Recently, prospective human studies have been used to define TCR families associated with immunity to TB progression. Here, TCR families associated with protection from progression to disease were previously identified in Interferon Gamma Release Assay (IGRA) positive South African adolescents (ACS). While M. Musvovsi et al., were able to define three antigens associated with these TCR families, we note that the majority remain unsolved. Furthermore, in our ongoing work with Cascade IMPAcTB using samples that were previously collected, we will define TCR families associated with protection, within a household contact (HHC; Stellenbosch) study. Specifically, to delineate lung inflammation, we are using fluorodeoxyglucose (FDG) Positron Emission Tomography and Computed Tomography (PET-CT), a technique that uses high resolution anatomic imaging (CT) in conjunction with functional imaging that includes FDG as a marker of glucose uptake. HHC with a negative FDG PET-CT, representing protection (adaptive immune control), can be compared those with a positive FDG PET-CT, representing subclinical TB. In this study, TCR families and transcriptional profiling will be available from the lung and periphery. Finally, we will have the opportunity to evaluate the function of T cells recognizing identified protection-associated antigens in an independent cohort of active and latently infected adults in Portland, OR. Key questions to be addressed: 1. What are the TCR families associated with protection? 2. What are the antigens and epitopes recognized by protection-associated TCRs? 3. What is the relative affinity of these TCRs for their cognate peptide? 4. What is the relative affinity of these TCRs for the Mtb-infected cell? 5. What is the functional profile of these cells? In this application, we will simultaneously test multiple mechanisms through which these protective TCRs mediate control: 1) specific TCRs could confer protection by targeting specific antigens, 2) protective TCRs could have higher relative affinity for their cognate antigen(s), which leads to enhanced recognition of the Mtb-infected cell, and 3) T cells expressing these protective TCRs may possess enhanced effector function.
