Intestinal lymphoid cells


Gérard EBERL, Team Leader
Caspar OHNMACHT, Postdoc
Sascha CORDING, Postdoc
Joo Hong PARK, Postdoc
Jasna MEDVEDOVIC, Postdoc

Intestinal lymphoid cells in innate and adaptive immunity

 

Aim

We have shown how a particular type of innate lymphoid cells (ILCs), termed lymphoid tissue inducer (LTi) cells, induces the development of lymph nodes and Peyer's patches in the fetus. These cells are characterized by the expression of the nuclear hormone receptor RORgt, and the production of pro-infammatory cytokines, such as LTa, LTb, TNF, TRANCE, IL-17 and IL-22. In fact, LTi cells induce a programmed inflammation in the sterile environment of the fetus, a process that is mimicked during infection and injury after birth by activated lymphocytes. RORgt is also expressed by a larger family of pro-inflammatory ILCs that abound in the intestine and play a critical role in intestinal homeostasis and defense. It is also expressed by Th17 cells, as well as subsets of Tgd cells, iNKT cells and Treg cells. We therefore aim at understanding the development and activation of RORgt+ cells, and their role in the development of lymphoid tissues, homeostasis and defense. More generally, we aim at deciphering the role of pro-inflammatory immunity not only during pathology, but also in maintaining homeostasis of the host.



The intestine is home to a large population of IL-17 producing T cells, termed Th17 cells. Through IL-17 and IL-22, these cells reinforce epithelial defense and containment of the vast symbiotic microbiota. The nuclear hormone receptor ROR
gt is expressed by Th17 cells and is required for their development and induction of the IL-17 program. Using the BAC-transgenic Rorc(gt)-GfpTG mice, we dissect the development and the role of the RORgt+ T cells in ontogeny, homeostasis, inflammation and defense.




RORgt+ (GFP+) T cells of the intestinal lamina propria (LPLs) and the mesenteric lymph nodes express IL-17 and FoxP3 (Lochner et al., J. Exp. Med. 2008)


Recently, it was discovered that the diverse subsets and functions of T helper cells are mirrored by innate lymphoid cells (ILCs). ILCs include NK cells that mirror Th1 cells, nuocytes that mirror Th2 cells and RORgt+ ILCs that mirror Th17 cells. In contrast to T cells, ILCs do not require selection and differentiation: they expand in particular cytokine contextes and display programmed functions shortly after the immune trigger. However, ILCs cannot provide antigen-specificity and memory.



Innate lymphoid cells (ILCs) are the functional mirror images of T cells.


We have shown that pro-inflammatory RORgt+ ILCs are programmed to secrete high levels of IL-17 and IL-22. After weaning, this function is repressed by microbiota through the expression of IL-25 by epithelial cells. Two types of RORgt+ ILCs develop in the mouse intestine: the lymphoid tissue inducer (LTi) cells, and the c-kit-low cells that include NKp46+ cells. LTi cells induce the development of secondary lymphoid tissues before birth and of isolated lymphoid follicles (ILFs) from intestinal cryptopatches after birth. C-kit-low cells develop mostly after birth and do not cluster in cryptopatches. They populate the intestinal lamina propria and may more directly interact with epithelial cells.



The programmed development of RORgt+ innate lymphoid cells (ILCs) that pre-empts bacterial colonization of the intestine (Sawa et al., Science 2010; Sawa et al., Nat. Immunol., 2011)


In the absence of RORgt, and therefore without the capacity to mount a pro-inflammatory response based on IL-17 and IL-22, mice are highly susceptible to DSS-mediated colitis, demonstrating the important role of RORgt-mediated immunity in the maintenance of intestinal homeostasis.



RORgt-deficient mice are highly susceptible to DSS-mediated colitis. The complementation of such mice with wild-type T cells, including Th17 cells, reduces inflammatory pathology (Lochner et al., J. Exp. Med. 2011).