Submitted to: Vaccine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/3/2007
Publication Date: 10/23/2007
Citation: Endsley, J.J., Hogg, A., Shell, L.J., Mcaulay, M., Coffey, T., Howard, C., Capinos-Scherer, C.F., Waters, W.R., Nonnecke, B.J., Estes, D.M., Villarreal-Ramos, B. 2007. Mycobacterium bovis BCG Vaccination Induces Memory CD4+ T cells Characterized by Effector Biomarker Expression and Anti-mycobacterial Activity. Vaccine. 25(50):8384-8394. Interpretive Summary: Despite highly successful eradication efforts in several countries, tuberculosis of cattle remains a serious health concern worldwide. In addition, recent outbreaks of tuberculosis in Michigan, California, Texas, Minnesota, and New Mexico demonstrate that the disease is far from eliminated from the United States. Improved strategies are needed for the control of tuberculosis in cattle. To develop these strategies, it is beneficial to first understand the immune response to infection. In this study, specific host responses of cattle to tuberculosis were determined. Specifically, a potential correlate to protective immunity is described. Knowledge obtained from this study will assist in the development of new diagnostic tests and vaccines for the control of tuberculosis of cattle.
Technical Abstract: The immune responses mediated by interactions between T-lymphocyte subsets and mycobacteria-infected macrophages (M-phi) are critical for control of tuberculosis (TB). Activation of M phi-mycobactericidal activity by IFN-gamma has been shown to play an important role in protection against mycobacteria in humans and in other species. Cytotoxic effector mechanisms are also thought to play a role in the control of mycobacteria by CD4+ T-cells in humans, non-human primates, and cattle. The absence of a full complement of cytolytic granule components precludes the use of the murine model for the characterization of the cytolytic/bactericidal T lymphocyte effector repertoire elicited by BCG vaccination. In these studies, the bovine model was used to characterize the cytolytic and mycobactericidal CD4+ T cell response induced by BCG vaccination. Three days following BCG boosting of M. bovis BCG primed animals, increased transcription of granulysin, perforin, and IFN-gamma in draining lymph nodes relative to non-draining lymph nodes was observed. Antigenic stimulation of peripheral blood CD4+ T-cells from BCG vaccinated cattle induced expression of perforin and IFN-gamma in cells expressing a CD45RA-, CD45RO+, and CD62L+ cell surface phenotype. Increased antigen specific transcription of granulysin, IFN-gamma, perforin, IL-4, IL-13, and IL-21 was also detected. The kinetics of cytolytic/bactericidal T lymphocyte effector molecule gene expression following stimulation with specific antigen and mitogen revealed differences in post-activation regulation of granulysin compared to perforin and IFN-gamma. Following antigenic stimulation, CD4+ T cells, CD4+CD45RO+, and CD4+CD45RO- T cells from BCG vaccinated animals contributed to reduction of intracellular BCG in infected M-phi. There were no detectable effects of antigen presenting cell (macrophage or DC) or stimulating antigen (BCG or PPD-B) on expression of memory markers, effector molecules, or mycobactericidal properties. These results demonstrate that vaccination with BCG induces a subpopulation of mycobacteria-specific CD4+ T cells that are characterized by the expression of a cell-surface memory phenotype, enhanced expression of mycobactericidal molecules, and anti-mycobacterial activity against intracellular M. bovis BCG.