Intestinal migratory innate lymphoid cells

Kästele, Verena (2018) Intestinal migratory innate lymphoid cells. PhD thesis, University of Glasgow.

Abstract

Innate lymphoid cells (ILCs) mainly reside at mucosal sites, where they produce effector cytokines upon activation. ILCs are also found, at lower frequencies, in secondary lymphoid tissues. ILCs in the lymph nodes (LN) are located in the interfollicular area, which is rich in migratory dendritic cells (DCs) and recently activated T cells and B cells. We recently discovered that some intestinal ILCs traffic from the intestinal lamina propria to mesenteric lymph nodes (MLN). However, the functions of ILCs in the LNs are hardly understood. Here we provide for the first time a detailed description of the migratory ILCs in intestinal lymph of mice in homeostasis and immunity.

To isolate migratory ILCs, we obtained lymph by thoracic duct cannulations of mice with or without a previous mesenteric lymphadenectomy. The ILC populations were then analysed by flow cytometry, and their transcriptomic profile was assessed by performing RNA sequencing. Our results show that a small number of migratory ILCs continuously traffic from the intestine to the MLNs. Whole genome analyses in the steady state revealed a shared global ILC signature between migratory ILCs in lymph and intestinal resident ILCs. We then demonstrated that all subsets of ILCs migrate in intestinal lymph, with ILC1 and ILC2 being most frequent. We compared the transcriptomic profile of migratory DCs, T cells and ILCs in afferent lymph and clearly identified a core migratory signature shared by all cell types. In order to investigate the impact of inflammation on this migratory ILC population, we used several infection and inflammation models, and assessed changes in the migratory ILC populations. We detected phenotypic changes of migratory ILCs following Salmonella infections of mice. Furthermore, although Salmonella infection did not increase total numbers of migratory ILCs in lymph, we observed an increase in T-bet+Roryt+ co-expressing ILCs in lymph of infected mice. After infection, changes in ILCs transcriptomic profile indicate an activated phenotype. Corresponding to the lymph ILC data, we also observed an accumulation of T-bet+Roryt+ co-expressing ILCs in the colonic draining LN (cMLN). Our data clearly demonstrate, for the first time, that inflammation can alter migratory ILC populations. This might be important for the initiation and regulation of adaptive immune responses in the draining LN. This first characterisation of migratory ILCs is important as it helps to understand how they contribute to shaping adaptive immune responses in the interfollicular area of the LNs.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Innate lymphoid cells, intestine, migration, Salmonella infection.
• Subjects: Q Science > QR Microbiology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Immunology & Infection
• Supervisor's Name: Milling, Professor Simon and Withers, Dr. David
• Date of Award: 2018
• Embargo Date: 20 July 2021
• Depositing User: Verena Kästele
• Unique ID: glathesis:2018-30723
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 08 Aug 2018 11:33
• Last Modified: 11 Aug 2022 10:08
• Thesis DOI: 10.5525/gla.thesis.30723
• URI: https://theses.gla.ac.uk/id/eprint/30723