|Jacobs Jr., William|
Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 8/25/2009
Publication Date: 8/25/2009
Citation: Estes, D.M., Palmer, M.V., Nonnecke, B.J., Thacker, T.C., Jacobs Jr., W.R., Larsen, M.H., Endsley, J.J., Hogg, A., Shell, E., Mcalauy, M., Capinos-Scherer, C.F., Coffey, T., Howard, C.J., Villareal-Ramos, B., Waters, W.R. 2009. Innate and Adaptive Cytotoxic Lymphocytes and Prognostic Markers of Host Responses to Bovine TB [abstract]. Interpretive Summary:
Technical Abstract: Cell mediated immunity (CMI) is essential for protection against TB in cattle, as in human disease. The cellular and molecular mechanisms of the bovine CMI responses to TB have been characterized during efforts to develop vaccines for cattle. These studies have identified similarities in mechanisms of anti-mycobacterial CMI among human and bovine systems, including the roles of T cell subsets (CD4+, CD8+, and gamma-delta TCR+), the protective function and cellular sources of IFN-gamma and cytotoxic granule proteins, the reduction of mycobacterial numbers by cytotoxic T cells and NK cells, the levels of antigen specific Th1 and Th2 cytokines, and the expression of memory markers by antigen specific T cells. Antigen-induced release of IFN-gamma is a pivotal component of the CMI response to TB in cattle, as well as in human and all other animal models of TB. In cattle, antigen-specific expression of IFN-gamma by total and memory T cells is associated positively with the degree of protection conferred by vaccines. In comparison to rodents, immunity of humans and cattle to TB appears to be less reliant on IFN-gamma induced activation of macrophages and more dependent on cytotoxic immune cells (CTL).. Bactericidal activity of bovine peripheral blood mononuclear cells, as well as isolated CD4+ and CD8+ T cell subsets, against M. bovis-infected targets, indicates CTL activity is a conserved mechanism of protective immunity to TB across species. Memory CD4+ T cells (CD45RO+) from BCG-vaccinated animals are very efficient at reducing BCG numbers in infected macrophages following stimulation with antigen.. Anti-mycobacterial activity of the antigen-stimulated CD4+CD45RO+ subset induced by BCG vaccination in these studies correlated positively with perforin and IFN-gamma expression by the same memory subset. The role of natural killer (NK) cells in immunity to TB is controversial, as NK cell-deficient mice are not more susceptible to Mtb infection. The bovine neonate, as in the human neonate, has a larger percentage of circulating NK cells compared to adults. Bovine NK cells express many homologues of human NK cell surface molecules that mediate the balance between activation and inhibition signals required to control cytotoxic activity. Bovine NK cells can dramatically reduce M. bovis BCG numbers in infected alveolar macrophages or macrophages derived from blood monocytes. As in other species, activation of bovine NK cells through IL-2, IL-15, and IL-12 receptors results in greater expression of perforin and IFN-gamma, alterations in surface markers associated with activation and trafficking, and enhanced cytotoxicity. Comparative studies of bovine and human TB have significant potential for further defining the role of NK cells in protective immunity to mycobacteria.