Human immunity to M. tuberculosis: T cell subsets and antigen processing
Section snippets
Natural history of infection
Aerosolized M. tuberculosis bacilli are efficiently transmitted from person to person. Only small numbers of bacilli need enter distal alveoli of human lungs to establish infection. In most persons, local innate immunity, mediated primarily by alveolar macrophages, fails to control the slowly replicating bacilli. As a result, the immune system is exposed to increasing amounts of mycobacterial antigen resulting in development of adaptive immunity. In most healthy adults, adaptive immunity
The central role of CD4+ T cells in protective immunity to
Studies in humans and animal models demonstrate that acquired immunity to M. tuberculosis requires contributions by multiple T cell subsets, which include a dominant role for CD4+ T cells and significant roles for CD8+ and γδ T cells.1 The reasons for involvement of these multiple T cell subsets are not known. Diversity in T cells that differ in antigen processing mechanisms and molecules used for antigen presentation greatly expands the repertoire of mycobacterial antigens recognized. The
MHC class I restricted CD8+ T cells
CD8+αβTCR+ T cells (CD8+T cells) are activated by M. tuberculosis and BCG.39., 40., 41. M. tuberculosis reactive CD8+ T cells are found among alveolar and peripheral T cells of healthy tuberculin skin-test positive persons.39 M. tuberculosis activated CD8+ T cells secrete IFN-γ, but less than CD4+ T cells.40 They express granzymes, Fas-L (CD95L), granulysin, and perforin, which enables them to lyse infected macrophages.19 CD8+ T cells can help macrophages control intracellular mycobacteria.
γδ T cells and other T cell populations
γδ TCR expressing T cells (γδ T cells) are characterized by a unique T cell antigen receptor (TCR) comprised of γ and δ chains. The majority of circulating γδ T cells in adults express Vδ9 (aka Vγ2) and Vδ2 elements (Vδ2+ T cells). M. tuberculosis bacilli readily activate Vδ2+ T cells.47 Similar to CD4 and CD8+ T cells, Vδ2+T cells secrete IFN-γ, can lyse infected macrophages and can help contain mycobacterial growth.17., 48. Individuals sensitized to mycobacterial antigens have a greater
T cell inhibition by
The complexity and diversity of the adaptive immune response to M. tuberculosis require development of mechanisms to interfere and inhibit host immunity for pathogen survival. M. tuberculosis evolved to survive and persist in key immune effector cells, the macrophage. Macrophages readily take up microbial pathogens, have effective microbicidal mechanisms, process and present antigens for T cell recognition, and express the necessary costimulatory molecules to activate T cells.
M. tuberculosis
Modulation of macrophage antigen-presenting cell function by
Recent studies suggest an important third way for M. tuberculosis to evade adaptive immune responses, namely interfering with antigen processing and presentation by macrophages. Processing of antigens is essential for T cells to recognize cells infected by microbes and is regulated by complex cellular processes resulting in peptide presentation by two distinct sets of molecules: MHC class II for CD4+ and MHC class I for CD8+ T cells. Little is known about inhibitors of antigen processing for
Acknowledgements
This work was supported by National Institutes of Health grants A127243 and HL55967, and contract A195383 to the Tuberculosis Research Unit.
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