The intestinal surface is daily challenged with tremendous amount of foreign material derived our diet and from the commensal bacteria that densely populate the mucosal surface. Occasionally the gut mucosa is exposed to pathogens trying to enter our body. The important task of the intestinal immune system is to remain tolerant toward innocuous luminal constituents and to elicit defense responses towards invading pathogens. Conventional dendritic cells (cDC) play a central role in the initiation of such tolerogenic and defense responses. They scan and sample the local environment, migrate to the draining lymph nodes, where they activate adaptive immune cells specifically recognizing the presented luminal antigens. Several subsets of cDC populate the intestinal mucosa, but their role in the adaptive immune response is incompletely defined. The present Ph.D. thesis aimed to identify some of the in vivo functions of intestinal cDC subsets in the generation of adaptive immune responses.
In paper 1, we demonstrated that cDC1 play a critical role in the homoeostasis of various subsets of intestinal T cells. In particular, we could show that cDC1 are crucial for the differentiation of Th1 cells and for the generation of conventional CD8αβ+ and cytotoxic-like CD4+CD8αα+ IEL, the latter requiring β8-integrin expression on cDC1. Lack of cDC1 in the MLN, was associated with impaired priming and reduced induction of small intestinal homing receptors on responding antigen-specific CD8αβ+ T cells. Collectively these results highlight multiple non-redundant roles for cDC1 in the maintenance of intestinal T cell homeostasis.
In paper II, we demonstrate that a fraction of small intestinal CD103+CD11b+ cDC specifically expresses glycoprotein 2 (GP2). GP2 is a GPI-anchored protein previously found to be expressed by M-cells in the intestinal epithelium and to act as a receptor for type-I fimbriae on bacteria. The presence of GP2+ cDC in the intestine was dependent on expression of the transcription factor IRF4 and was regulated by the microbiota and aryl hydrocarbon receptor signaling. cDC-derived GP2 was not required for normal intestinal T cell homeostasis. The role of this molecule on cDC remained unidentified, but it may potentially be involved in uptake of type-I fimbriated bacteria and in regulation of adaptive immune responses.
In paper III, we addressed the role of intestinal cDC subsets in the initiation of B cell responses toward systemically administered flagellin (FliC). Mice lacking cDC2, but not cDC1, failed to induce the differentiation FliC-specific IgA and IgG plasma cell in the MLN, correlating with abrogated formation of FliC-specific germinal centers. Thus, intestinal cDC2 play a crucial role in the generation of antibody responses toward FliC.
Collectively, the work performed in present Ph.D. thesis has broadened our understanding on the in vivo functionality of intestinal cDC subsets in the generation of adaptive immune responses.
- Department of Experimental Medical Science
- Agace, William, Supervisor
- Johansson Lindbom, Bengt, Supervisor
|Award date||2018 Feb 2|
|Place of Publication||Lund|
|Publication status||Published - 2018|
Place: Belfragesalen, BMC D15, Klinikgatan 32 i Lund
Name: Reis e Sousa, Caetano
Affiliation: The Francis Crick Institute, London
Lund University, Faculty of Medicine Doctoral Dissertation Series 2018:9
- Medical and Health Sciences
- Natural Sciences