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Exploring the roles and plasticity of T-cell responses in anti-BACterial immunity

Final Report Summary - T-BAC (Exploring the roles and plasticity of T-cell responses in anti-BACterial immunity)

Understanding the functional properties and phenotypic plasticity of anti-bacterial CD4+ T-cells may be crucial for the development of some anti-bacterial vaccines [Bagnoli F et al, Front Cell Inf Microbio 2012; Proctor RA, Clin Infect Dis 2012; Spellberg B et al, Semin Immunopathol 2012]. In particular, for Staphylococcus aureus (S. aureus) there is a need to define immune correlates of protection because S. aureus vaccine candidates aiming at inducing antibody responses did not show consistent protective efficacy in humans [Bagnoli F et al, Front Cell Inf Microbio 2012; Proctor RA, Clin Infect Dis 2012; Spellberg B et al, Semin Immunopathol 2012]. It has been hypothesized that Th17 cells may be important: this is supported by the fact that patients suffering from hyper-IgE syndrome have a deficiency in their Th17 responses and are abnormally susceptible to S. aureus infections [Ma CS et al, J Exp Med 2008; Milner JD et al, Nature 2008]. Th17 cells are characterized by the production of the pro-inflammatory cytokine IL-17A and display considerable phenotypic plasticity [Zhou L et al, Immunity 2009]. Recent published data also suggested that regulatory mechanisms may play a role during S. aureus infection. Mortality in patients with S. aureus bacteremia was linked to high level of circulating IL-10 [Rose WE et al, JID 2012]. In addition, both monocytes and T cells stimulated in vitro with S. aureus were shown to produce IL-10 [Wang J et al, Sci Rep 2012; Zielinski et al, Nature 2012]. The complexity of the immunological response to S. aureus implies that translation of the fundamental science into vaccine development requires a better understanding of these T cell lineages and their role in anti-bacterial host defense. Using S. aureus as a model and hypothesizing that the functional profiles of CD4+ T-cells may be linked to selected bacterial proteins, we aimed to: (i) identify novel S. aureus T cell antigens; (ii) characterize the immune responses to these S. aureus antigens and study the plasticity of the induced T cells; (iii) To evaluate the impact of vaccination on phenotypes and functionality of S. aureus-specific cells.
Based on literature review and bioinformatics analysis, 10 proteins were selected and successfully produced. These included toxins, proteins binding extracellular matrix and proteins involved in metal uptake and cell wall metabolism. Healthy donor PBMC samples were then stimulated with these 10 individual proteins. Overall, all the proteins were able to induce the expression of IFN-γ in the majority of the donors tested while only 3 antigens were able to expand S. aureus-specific Th17 cells. IL-22 was poorly expressed in CD4 T cells and IL-10 was undetectable. However, IL-10 was present in the supernatants of cells stimulated with inactivated S. aureus. Phenotypic analysis showed that IL-10 was produced by innate immune cells expressing several markers of tolerogenic monocytes and dendritic cells.
In order to study the plasticity of Th17 cells we cultured healthy donor PBMCs with Th17 inducing antigens and with or without modulatory cytokines, such as the combination of IL-12/IL-18, IL-27 and IL-10. The results showed that Th17 cells retain a certain degree of plasticity: IL-17 production could indeed be modified by the presence of the above-mentioned cytokines.
We were in the unique situation to have access to samples from a clinical trial [ NCT01160172] in which healthy donors were immunized with adjuvanted or non-adjuvanted investigational S. aureus vaccines. Experiments performed on these samples showed that the vaccine antigens were able to expand pre-existing IFN-γ responses. Th17 cells however were not induced by the vaccine, even in the presence of the adjuvant.
Current vaccines are based on the induction of functional antibodies that might, however, not be sufficient for anti-bacterial host defense. The T-BAC project helped to define the S. aureus antigens able to induce T cell responses. This is beneficial not only for the development of a vaccine against S. aureus but in general as a strategy to develop new vaccines in which T cell immunity may be important for protection. The T-BAC project brought new insights into Th17 immunology. In addition, it helped understanding how cytokines modulate memory T cell responses, in particular how IL-10 can modulate Th1 and Th17 subsets. The knowledge gained from T-BAC can be beneficial for many other projects in which Th17 cells or regulatory mechanisms may play a role. Overall, understanding the nature of anti-bacterial T cells and their behavior in steady state or under inflammatory conditions might change the way vaccines will be designed in the future.