von Burg, Nicole. Characterization of group 3 innate lymphoid cell function in the innate and adaptive immune system. 2015, PhD Thesis, University of Basel, Faculty of Science.
Restricted to Repository staff only until 1 July 2017.
Official URL: http://edoc.unibas.ch/diss/DissB_11343
In the present study, I could show that ILC3s directly responded to microbial products such as the Toll-like receptor (TLR) ligands CpG and Poly I:C in vitro. They up-regulated the surface expression of the early activation marker CD69 and secreted IL-22, a cytokine known for its protective immune function in the mucosa. Additionally, I could demonstrate that in vivo challenge with TLR ligands CpG and LPS was able to induce ILC3 activation in vivo. Furthermore, ILC3s produced high amounts of IL-17 and IL-22 upon exposure to the pro-inflammatory cytokine IL-1β. IL-1β emerged as a strong activator of ILC3s as its presence induced the production of a broad range of cytokines by ILC3s. Altogether, the response of ILC3s varied depending on the nature of innate stimuli.
In addition, I could demonstrate that upon IL-1β exposure, peripheral ILC3s up-regulated the expression of surface major histocompatibility complex class II (MHC II) molecules and expressed co-stimulatory molecules reminiscent of an antigen-presenting cell-like phenotype. Further, I found that ILC3s could take up latex beads, process protein antigen (Ag) and consequently prime CD4+ T cell responses in vitro. The cognate interaction of ILC3s and CD4+ T cells led to T cell proliferation both in vitro and in vivo. By using a mouse model with MHC II deficiency exclusively in ILC3s I could demonstrate that the disruption of Ag-dependent interaction of ILC3s and CD4+ T cells impaired specific T cell and T-dependent B cell responses in vivo. In addition, I found that IL-1β-activated peripheral ILC3s were more efficient than non-activated ILC3s in the induction of CD4+ T cell responses. ILC3-CD4+ T cell interactions turned out to be bidirectional and led to the activation of ILC3s. The activating feedback loop of CD4+ T cells to ILC3s was most likely mediated by soluble factors produced by CD4+ T cells upon Ag encounter. Taken together, my data reveal an activation-dependent function of peripheral ILC3s in eliciting cognate CD4+ T cell immune responses, ascribing to them a novel function in adaptive immunity.
Finally, I found that small intestinal ILC3s and peripheral ILC3s differed from each other in regard to their phenotype, responsiveness to IL-1β and immune function. In contrast to peripheral ILC3s, small intestinal ILC3s expressed high levels of CD69 on their surface suggesting an activated phenotype. I could show that CD69 expression was independent of TLR- and IL-1R signaling, the presence of T and B cells, or the microbiota as well as the availability of IL-23. In addition, small intestinal ILC3s were not able to increase the expression of MHC II molecules and to express co-stimulatory molecules upon IL-1β exposure. Although they were able to take up latex beads and to process exogenous Ag, they were far less efficient in CD4+ T cell activation than peripheral ILC3s. However, they were capable to produce high amounts of IL-22 in response to IL-1β stimulation. Taken together, these data suggest that the immune functions of ILC3s are tissue specific and might be regulated by environmental factors and/or interactions with tissue-specific cells.
|Committee Members:||Rolink, Antonius G.|
|Faculties and Departments:||03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Children's Hospital > Developmental Immunology (Finke)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||196 p.|
|Last Modified:||30 Jun 2016 10:58|
|Deposited On:||05 Oct 2015 14:07|
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