T cell recognition to Mtb infected macrophages

Following virulent Mycobacterium tuberculosis (Mtb) infection in mice, a robust T cell response is primed and recruited to the lung. There, T cells restrict Mtb growth, which leads to a plateau in the bacillary burden. Despite T cell dependent clearance of most bacilli, sterilization is never achieved. Under optimal conditions, the best vaccines in the murine model provide only an additional 30-fold CFU reduction. Why does a relatively small, but biologically important subpopulation of bacteria persist in the face of otherwise effective T cell immunity? Our overarching hypothesis is that bacteria survive despite robust T cell responses because of a failure in T cell surveillance and effector function. For bacteria that infect mammalian cells, immune clearance relies on CD4 and CD8 T cells that recognize antigens sampled in endosomes (by MHC II) or the cytosol (by MHC I). Non-MHC restricted T cells (e.g., NKT, MAIT cells) also sample cellular compartments. A major scientific goal is to identify microbial antigens for use in vaccines. In the past, microbial antigens were identified based on their ability to be recognized by T cells. Immunization with such antigens would often elicit T cell responses, but few were protective. The frequent failure of microbial antigens to induce protective T cell responses was rationalized by a probabilistic view of immunology: “some antigens are protective, some are not”. While this may be a truism, we now know that intracellular pathogens evolved to evade detection by the immune system and avoid T cell recognition. Mtb has co-evolved with us for 15,000 years and has numerous mechanisms to evade detection and avoid killing by our immune system. Our inability to predict which Mtb antigens will be presented by infected cells is a major gap in selecting candidate antigens for vaccines. We are building upon our previous work at the host-pathogen interface to determine: 1) which T cells recognize infected macrophages; 2) which antigens are recognized; 3) how T cells restrict Mtb growth, and 4) how Mtb evades elimination.