Untersuchung der Mechanismen der DC-Lizensierung, die eine zytotoxische T-Zell-Antwort bei Virusinfektionen auslösen
Parasitologie und Biologie der Erreger tropischer Infektionskrankheiten
Zusammenfassung der Projektergebnisse
CD8+ T cell immunity is an important part of the adaptive immune response, especially for the fight against intracellular pathogens like HSV-1, influenza, and human immunodeficiency virus (HIV). It is crucial to understand the mechanisms underlying the priming of CD8+ T cells and factors influencing their transition into long-lived memory T cells. In my first project I have examined which cytosolic PRR pathways are involved in the priming of CTL following epicutaneous HSV-1 infection. The Bedoui lab has previously shown that priming of CTL relies on HSV-1 sensing by TLR3 but not other TLR. We could demonstrate that the recognition of viral DNA by the cytosolic adaptor molecule STING and the inflammasome complex AIM2 is negligible for the priming of HSV-specific CTL. In contrast, we could establish that the recognition of DNA by STING is involved in the immediate innate control of virus proliferation at the site of infection. Importantly, the recognition of HSV RNA intermediates by a MAVS-dependent pathway is essential for priming of CTL following infection. Furthermore, the transcription factor IRF-3 but not IRF-7 is involved in this process. In summary, our results demonstrate that innate sensing of HSV-1 RNA but not DNA and downstream signaling via type I IFN is decisive for effective priming of effector CD8+ T cell responses. For long-lasting protection against pathogens, effector CD8+ T cells need to develop into memory cells. The role of innate signals triggered by the interaction of immune cells with microbiota in this transition process is unclear. Building on unpublished results obtained by the Bedoui lab showing that effector CD8+ T cells fail to develop into circulatory memory CD8+ T cells when transferred into GF mice, we set-out to unravel molecules involved in this process. Firstly, we validated this key finding by demonstrating that the endogenous pool of memory CD8+ T cells is also significantly reduced in GF animals. Furthermore, we utilized RNA sequencing of transferred effectors in their transition phase to memory CD8+ T cells from GF and SPF mice. Several genes were differentially expressed and to our surprise, T cells from GF animals expressed more message of itgαE, a gene encoding for the integrin CD103. We could confirm this finding by analyzing CD103 protein expression on transferred effector CD8+ T cells in GF animals using flow cytometry. Intriguingly, CD103 is usually not expressed by circulatory T cells but instead by TRM and is dependent on TGF-β. Using in vitro stimulation of effector CD8+ T cells, we could show that both, TGF-β and type I IFN can influence CD103 expression and therefore are molecules potentially signaling between microbiota and CD8+ T cells. We are currently testing the role of type I IFN, TGF-β, and several bacterial metabolites in this process and if T cells receive signals directly or by DC interacting with commensals.
Projektbezogene Publikationen (Auswahl)
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Cooperation between monocyte-derived cells and lymphoid cells in the acute response to a bacterial lung pathogen. PLoS Pathog. 12(6):e1005691
Brown, A.S., Yang C., Fung K.Y., Bachem A., Bourges D., Bedoui S., Hartland E.L. and van Driel I.R.
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T Cell Help Amplifies Innate Signals in CD8(+) DCs for Optimal CD8(+) T Cell Priming. Cell reports 14, 586-597 (2016)
Greyer, M., Whitney P.G., Stock A.T., Davey G.M., Tebartz C., Bachem A. et al.
