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Characterization of group 3 innate lymphoid cell function in the innate and adaptive immune system

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.

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Official URL: http://edoc.unibas.ch/diss/DissB_11343

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Abstract

Group 3 innate lymphoid cells (ILC3s) play decisive roles in mammalian physiology including lymphoid tissue development, tissue repair and immune regulation. So far, the functions of ILC3s in the adult immune system have been mainly linked to their capacity to release cytokines in response to microbial or inflammatory signals. It could be demonstrated that ILC3s are indispensable for protective immunity against the mouse intestinal pathogen Citrobacter rodentium by the early production of IL-22 in response to IL-23 secreted mainly by dendritic cells (DCs) upon microbial exposure. However, whether ILC3s are able to directly sense and respond to the presence of pathogens thereby contributing to innate immunity is not yet known. Furthermore, whether these cells are capable to interact with cells of the adaptive immune system to meaningfully regulate adaptive immune responses has to be explored.
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.
Advisors:Finke, Daniela
Committee Members:Rolink, Antonius G.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Children's Hospital > Developmental Immunology (Finke)
Item Type:Thesis
Thesis no:11343
Bibsysno:Link to catalogue
Number of Pages:196 p.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:58
Deposited On:05 Oct 2015 14:07

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