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Location: Infectious Bacterial Diseases Research

Title: The immune response to bovine tuberculosis: Correlates of protection and relevance to human tuberculosis

item Waters, Wade

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 10/30/2013
Publication Date: 12/5/2013
Citation: Waters, W.R. 2013. The immune response to bovine tuberculosis: Correlates of protection and relevance to human tuberculosis [abstract]. Australasian Society of Immunology. Abstract #019.

Interpretive Summary:

Technical Abstract: Tuberculosis (TB), primarily due to Mycobacterium tuberculosis in humans and Mycobacterium bovis in cattle, is a classic model for demonstration of the One Health Concept. Early studies with cattle were instrumental in the development of the use of Koch’s tuberculin as an in vivo measure of cell-mediated immunity for diagnostic purposes. Calmette and Guerin demonstrated the efficacy of an attenuated M. bovis strain (BCG) in cattle prior to use of this vaccine for TB in humans. The interferon-gamma release assay, now widely used for TB diagnosis in humans, was developed in the late 1980s for use in the Australian bovine TB eradication program. More recently, M. bovis infection and vaccine efficacy studies with cattle have demonstrated a correlation of vaccine-elicited T cell central memory (TCM) responses to vaccine efficacy, correlation of specific antibody to mycobacterial burden and lesion severity, and detection of antigen-specific IL-17 responses to vaccination and infection. Additionally, positive prognostic indicators of bovine TB vaccine efficacy (i.e., responses measured after infection) include: reduced antigen-specific IFN-gamma, iNOS, IL-4, and MIP1-alpha responses; reduced antigen-specific expansion of CD4+ T cells; and a diminished activation profile on T cells within antigen stimulated cultures. Delayed type hypersensitivity and IFN-gamma responses correlate with infection but do not necessarily correlate with lesion severity whereas antibody responses generally correlate with lesion severity. Long-term (i.e., 14d) cultured IFN-gamma responses of peripheral blood mononuclear cells are used as a correlate of Tcm responses in both humans and cattle. Recent studies with samples from M. bovis-infected cattle indicate that the long-term in vitro response to M. bovis specific antigens is primarily a measure of Tcm (~75%, i.e., CCR7+, CD45RO+, CD62Lhi) and T cell effector memory (Tem: ~24%, i.e., CCR7-, CD45RO+, CD62Lmod) responses whereas standard short term (i.e., 6d) responses are primarily a measure of T cell effector (~58%, i.e., CCR7-, CD62Llo, CD45RO-) and Tem (~40%) responses. Responding cells (Tcm and Tem) in the long-term cultured response are highly proliferative, exceeding the proliferative capacity of cells in the short-term cultured assay. In contrast to mice and humans, gamma delta T cells are a prominent subset of T cells in the peripheral blood of cattle. Beginning as early as 3 wks after experimental M. bovis infection, gamma delta T cells proliferate and produce IFN-gamma in response to non-protein and protein mycobacterial antigens - including small peptide antigens derived from immunodominant M. tb-complex specific antigens, ESAT-6 and CFP10. This response requires direct contact with APCs; however, it is independent of MHC class II. gamma delta T cells from M. bovis-infected cattle also produce IL-17A. In contrast to results from mice, bovine CD4 T cells and not gamma delta T cells are the primary source of this critical pro-inflammatory cytokine. Comparative immunology studies including partnerships of researchers with veterinary and medical perspectives will continue to provide mutual benefit to TB research in both man and animals.