Initiation and Evasion of the Immune Response to Mycobacterium tuberculosis

A major problem in developing new immunologic approaches to control of tuberculosis, such as a new vaccine, is the ability of Mycobacterium tuberculosis to avoid elimination by the immune response. It is known that partial protective immunity to tuberculosis develops in humans and in experimental animals infected with M. tuberculosis. This immunity is sufficient to arrest progressive disease, and optimal immunity requires CD4⁺ and CD8⁺ T lymphocytes, TNF, IL-12, and IFNγ. In experimental animals, and in most humans, the immune response is not able to eliminate M. tuberculosis and provide sterile immunity, which allows reactivation and transmission of infection later in life. Despite considerable effort, the mechanisms of initiation of the immune response to M. tuberculosis, and the mechanisms that allow M. tuberculosis to avoid elimination by the immune response, are incompletely understood.

The first part of the seminar will present our recent results, using adoptive transfer of CD4⁺ T cells that express a transgenic T cell antigen receptor that is specific for a peptide from M. tuberculosis Antigen 85B (provided in a collaboration with Professor Takatsu), to determine the in vivo location and kinetics of the adaptive immune response to M. tuberculosis.

The second part of the seminar will present results of recent studies that have revealed that M. tuberculosis infected diverse subsets of antigen-presenting cells in vivo. These experiments were accomplished by infection of mice with a strain of M. tuberculosis that expresses green fluorescent protein (GFP), and detection and phenotyping of infected cells by flow cytometry. We have found that M. tuberculosis infects dendritic cells in the lungs and in the lung-draining lymph node that express high levels of MHC class II and serve as efficient antigen-presenting cells to Antigen 85B-specific CD4⁺ T cells. In addition, we have found that M. tuberculosis infects macrophages in the lungs that express low levels of MHC class II, low levels of costimulatory molecules, and are poorly recognized by Antigen 85B-specific CD4⁺ T cells. The MHC class II-low macrophages contain more bacteria per cell than do the dendritic cells, and we hypothesize that they provide an immune-privileged location that allows M. tuberculosis to persist despite development of an adaptive immune response.