Hogg, A.E.; (2006) The nature of memory CD8+ T-cell responses in bovine tuberculosis. Doctoral thesis , University of London.

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Abstract

M. bovis is a zoonosis and is the aetiological agent of bovine TB. The incidence of bovine TB in the UK is increasing, demonstrating that the current test and slaughter policy is failing. M. bovis-BCG, the vaccine used against human TB, is not used in cattle as it interferes with the tuberculin skin test and only confers partial protection. The control of bovine TB will require the design of a more efficacious vaccine and discriminatory diagnostic test. To achieve this, a greater understanding of both the immune response induced by the mycobacteria and the protective immune response required to clear or control M. bovis infection in cattle is needed. In human and mouse studies, CD8+ T cells have been proposed to play an important role in immunity to mycobacteria. The aim of this study was to identify and define the CD8+ T cells induced by BCG vaccination and/or M. bovis infection in cattle. Initial experiments identified different subsets of CD8+ T cells present in cattle using expression of surface and effector molecules. The CD8+ population is heterogeneous and contains ap (TCR1"CD3+), y8 (TCR1+CD3+) and NK (TCRTCD3") cells. CD8+ cells could be divided into CD8hiCD3+ and CD8loCD3+/ The (CD8hiTCRT) ap+ T cells were analysed in this study as these form part of the adaptive immune response. Age-related increases in the percentage of activated/memory CD8hlTCRl" T cells were observed in blood as shown by increases in expression of the activation marker CD25 and memory marker CD45RO. Concomitant decreases were observed in the percentage of CD8hiTCRlT cells that express CD45RA, CD62L and CD27, surface molecules associated with naive T cells. The percentage of CD8hiTCRl" T cells in blood expressing perforin and IFN-gamma also increased with age. The CD8hlTCRlT cells present in the BAL were mainly activated/memory T cells as shown by a combination of expression of surface and effector molecules. In contrast, the CD8hlTCRlT cells present in the lymph nodes more resembled naive T cells with only a small percentage expressing perforin and IFN-gamma. A minor population of CD8hiTCRl"CD45RO+CD62L+ T cells were present in the LN which may be the bovine equivalent of murine central memory cells. BCG vaccination of cattle induces mycobacteria-reactive CD8hlTCRl"CD45RO+ T cells. These cells mediated recall responses to BCG, detected by proliferation, production of IFN-gamma, up-regulation of perforin expression and lysis of BCG-infected hi + macrophages (M). M. bovis reactive-CD8mTCRl"CD45RO T cells were detected in non-vaccinated and BCG-vaccinated animals after infection with M. bovis. These cells proliferated and produced IFN-gamma in response to M. bovis-infected but not BCG-infected M( ), indicating that they were responding to an M. bovis-specific antigen. Post- challenge responses in the CD8hiTCRl'CD45RO+ T cells from BCG-vaccinees were considerably greater than those of non-vaccinated animals. M 6ov/s-reactive CD8hiTCRl"CD45RO+ T cells reduced mycobacterial viability when cultured with BCG- or M. bovis-infected M( >. CD8hiTCRl"CD45RO+ T cells present in the lungs of M. bovis-infected animals expressed IFN-gamma after culture with mycobacteria. These results demonstrate that mycobacteria-reactive CD8hiTCRl"CD45RO+ T cells that express effector functions are present at the site of infection, and may contribute to the control of M. bovis infection in cattle. This study provides a basis to investigate the role of CD8hiTCRl"CD45RO+ T cells in immunity to M. bovis infection in cattle and to evaluate the effectiveness of new TB vaccines at inducing CD8+ T cell responses.

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