Durand, V.M.M.; (2005) Shaping of adaptive immune responses to soluble protein antigens by pathogen-associated molecular patterns. Doctoral thesis , University of London.

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Abstract

Invading organisms are detected by the innate immune system, through the recognition of conserved microbial structures. Innate responses are known to influence the development of adaptive immune responses, which are crucial for preventing infection and eliminating pathogens. Characterising the signals that initiate the induction of efficient cellular and humoral adaptive immune responses is particularly relevant for the rational design of new vaccines. The aims of this study were first to assess the ability of a broad range of conserved microbial stimuli to induce CD8+ T cells responses by cross-priming and enhance antibody responses against exogenous soluble protein antigens, and secondly to investigate the mechanisms by which microbial stimuli induced cross-priming. Stimulation of Toll like receptors (TLR) is believed to play a major role in the activation of innate and subsequent adaptive responses. All TLR agonists tested enhanced antigen-specific antibody responses, and in particular zymosan (TLR2/6), poly(I:C) (TLR3), LPS from E. coli (TLR4) and CpG DNA (TLR9) promoted IgG2a responses, which are thought to contribute effectively to protective mechanisms against pathogens in mice. However, only poly(I:C), LPS from E. coli and CpG DNA were able to stimulate the induction of cross-priming, whereas zymosan, peptidoglycan (TLR2/) and R-848 (TLR7) were ineffective. It is known that LPS from different bacteria species can elicit different immune responses. LPSs from Klebsiella pneumoniae and from Neisseria meningitidis, but not the unconventional LPS from Porphyromonas gingivalis, were able to induce cross-priming. Microbial mannose structures, as present in yeast mannan, Influenza hemagglutinin and polymannose LPS, were demonstrated for the first time to be able to induce functional cross-priming. In addition, mannan and polymannose LPS were found to enhance antigen-specific antibody responses and promote IgG2a responses. IFN-a/p and signalling through costimulatory molecules play a central role in the licensing of cross-priming. Experiments using knock-out mice showed that in all cases licensing of cross- priming was dependent on IFN-a/pR signalling, albeit to a varying degree. In contrast, signalling through CD40 was not required for induction of cross-priming by mannan and polymannose LPS. Induction of cross-priming by LPS from E. coli and by mannan was TLR4-dependent, whereas induction by polymannose LPS was TLR4-independent. This study thus identifies LPS from some bacteria species as cross-priming-inducing stimuli. It also confirms that activation of TLR can initiate induction of cross- priming, while indicating the existence of TLR-independent pathways. In addition, this work illustrates the importance of IFN-oc/pR signalling as a cross-priming licensing stimulus.

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