Neonatal vaccination: role for innate immune cell interactions in BCG vaccination
Hamilton, Carly Anne
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Bovine tuberculosis (TB), caused by Mycobacterium bovis, is increasing in incidence in the United Kingdom and detailed knowledge of host-pathogen interactions in the natural host is essential to facilitate disease control. Vaccination of neonatal calves with Bacille Calmette Guerin (BCG) induces a significant level of protection from infection with M. bovis. Since neonatal vaccination of humans with BCG induces activation of natural killer (NK) cells, and neonatal calves have high circulating numbers of these cells, it is proposed that NK cells are important in the response to BCG. Furthermore, NK cells play an important role in shaping adaptive immune responses through interactions with dendritic cells (DCs). The overall hypothesis of this project was that the enhanced efficacy of BCG in neonates is due to the increased number of NK cells, which through interactions with DCs can polarise Th1-type CD4+ and CD8+ T cell responses, both of which are involved in protection against M. bovis infection. Initially, the frequency and phenotype of NK cells across the blood, afferent lymph and the lymph nodes in steady-state conditions were compared. CD2- NK cells were the principal subset of NK cells migrating from the skin to the draining lymph node and were highly activated in afferent lymph and lymph nodes, compared with peripheral blood. It was also demonstrated that CD2- NK cells were the main subset of NK cells egressing from the lymph node via the efferent lymphatic vessel to return to circulation. Since many vaccines including BCG are delivered subcutaneously, NK cell responses in the blood and the skin draining afferent lymphatic vessel, lymph nodes and efferent lymphatic vessel were determined after BCG vaccination. Alterations in the frequency and receptor repertoire were evident following vaccination, supporting a role for NK cells during BCG vaccination of neonatal calves. To investigate the interactions of NK cells and BCG-infected DCs, in vitro co-cultures were established. CD2- NK cells were preferentially activated following culture with BCG-infected DCs and secreted high levels of IFN-γ. Overall, this thesis provides novel evidence that NK cells may re-circulate in steady-state conditions, play a role in BCG vaccination of neonatal calves, and that through interactions with BCG-infected DCs, may be involved in driving protective Th1-type adaptive immune responses.