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An immune response to microbes and vaccines is initiated when a dendritic cell (DC) takes up an antigen, becomes activated and presents it to naïve (CD4+) T helper (Th) cells. Th cells begin to proliferate and differentiate into specialized Th subsets (e.g. pro-inflammatory Th1, Th2, Th17 or anti-inflammatory regulatory T cells – Tregs) which help to establish humoral or cellular immunity or tolerance. Due to their central role in this multistep process, T cells are known to be at the core of immunological effector mechanisms. Since T cells are not only responsible for controlling tumor cells and pathogens, but also provide important mechanisms of tissue repair, we mainly focus on T cells and the direct and indirect impact of microbial factors on T cell-mediated immunity as a central and unifying theme of our work.
As DCs are the major players initiating T cell responses and influencing T cell differentiation, we study the first steps of host-pathogen interaction at the DC level in various bacterial, viral and fungal infection models. DCs are part of the innate immune system that recognize microbial-associated molecular patterns (MAMPs) from pathogens via so-called pattern recognition receptors and are at present crucial target cells for vaccination. Our previous work has led to the discovery of several MAMPs and, in part, their introduction into the clinic as new potent adjuvants. Using novel genetic models (BAC / CRISPR technology) we try to address the following questions: Which roles do the various and highly-specialized sub-types of DCs play in different infections? What significance do certain pattern recognition receptors have for DC activation, antigen uptake and the corresponding T cell responses? How can we exploit this knowledge for more specific, safer adjuvants and better DC targeting approaches?
Controlling an immune response is just as crucial and this is where regulatory T cells (Tregs) play an exceedingly important role. On the one hand, these protect from overshooting immune responses and can prevent immunopathology, for example during chronic infections, allergy and autoimmune reactions. In the future, adoptive transfer of patient-derived Tregs could therefore represent a crucial aspect of individualized infection medicine. On the other hand, Tregs may be exploited by certain pathogens as they are induced during e.g. mycobacterial and certain viral infections and prevent pathogen clearance. In addition, there is strong evidence that Tregs inhibit tumour rejection. An optimal vaccination approach should incorporate strategies that would activate DCs and prevent Tregs from slowing down an adequate immune reaction without inducing autoimmunity. With our DEREG model we have significantly contributed to the understanding of T cell biology, particularly the importance of Tregs in the control of immune responses during inflammatory processes. Still, our knowledge on how Tregs differentiate, suppress and are regulated in a microbe-rich microenvironment, such as the site of infection or in the presence of commensal bacteria, is in its infancy. Moreover, manipulation of T cell immunity as a therapeutic strategy remains an uphill challenge and a central theme of our future efforts.
Deciphering the human Microbiome was thought to offer novel diagnostic and therapeutic avenues for almost any chronic illness of the ageing European, a premature hope as the complexity of the Microbiome is surpassed by far by the complexity of the metabolites produced by various commensals and pathogens. Understanding the Metabolome, the molecular language between microbiota and their mammalian hosts, may offer mechanistic clues as to how bacteria influence our immune system and contribute to inflammation and tolerance, reflecting one of the biggest challenges for future research. There are strong indications that the microbial Metabolome, which is extremely diverse and remains largely undefined, will provide a tremendous arsenal of new powerful immune modulators. Rapamycin is an excellent example, a drug isolated from Streptomyces species discovered on Rapa Nui and now in clinical use as a potent immunosuppressant, suggesting that the Microbiome has co-evolved various gene clusters coding for immunologically active compounds. The number of potential gut bacterial metabolites is presently unknown, comprising molecules of dietary, host and microbial origin entangled in a complex, fascinating interplay between host, bacteria and the immune system. Making use of a unique library of bacterial metabolites, we have identified promising candidates which directly and indirectly impact on T cell function and differentiation. To address the urgent need of understanding the Metabolome, we plan to specifically focus on commensals and important human pathogens and their intricate crosstalk with the host via novel metabolites. We propose here the term ‘meta-MAMPs’ to classify microbial-derived metabolites which impact on the immune response by affecting specific cellular processes. The study of meta-MAMPs may not only comprise the first step into fundamentally novel therapies against infectious / inflammatory disorders affecting the ageing European society, but will also contribute to our current knowledge on the regulation of T cell fate and function.
Fig.: Soraphen A shifts T cell development from inflammatory Th17 towards Treg cells by targeting the cellular fatty acid metabolism. To start the animation please click here.