The impact of migratory routes on intestinal tolerance in neonatal and adult mice
Final Report Abstract
In this project we have explored mechanisms that allow the gut immune system to tolerate innocuous antigen such as food and the microbiota. Failure to establish tolerance to these antigens can lead to inflammatory bowel disease and food allergies. Thus, a mechanistic understanding of the processes mediating intestinal tolerance holds the promise to eventually design targeted therapies to re‐install tolerance in patients with intestinal pathologies. Regulatory T cells are a key factor to ensure intestinal tolerance and in previous work, we have contributed to detail the mechanisms that enable the gut immune system to generate regulatory T cells. Central to our working model of regulatory T cell generation and intestinal tolerance, we suggested that regulatory T cells are generated in a multi‐step process that involves interactions between T cells and antigen presenting cells in different anatomical locations, firstly in the gut draining mesenteric lymph nodes and thereafter locally in the gut lamina propria. During the funded project we have focused on the interaction between T cells and antigen presenting cells, intestinal macrophages, in the gut lamina propria. We compared to phenotype and function of intestinal macrophages to macrophages in other compartments. This allowed us to establish a unique transcriptomic fingerprint characteristic of gut macrophages and to identify useful markers to characterize the state of these cells by flow cytometry. We carried on identifying factor that contribute to shape the unique function of gut macrophages. During this process, we focused on the cytokine transforming growth factor β (TGF‐β) and the integrin chain CD11b. We showed that TGF‐β substantially contributes to shape the intestinal macrophage phenotype but we also realized that additional factors seem to be involved and disruption of the TGF‐β signalling did not disrupt intestinal tolerance. To identify such factors, we compared monocyte to macrophage differentiation in heathy and inflamed small intestine. We observed that monocyte directly after entering the gut lamina propria sense environmental signal that instruct their differentiation into either tolerogenic of pro‐inflammatory macrophages, cells which either favor or counteract tolerogenic immune responses. Further work aim to define pathways that result in the accumulation of a regulatory T cell pool in the periphery. Teleological evidence suggested that regulatory T cells need to disseminate from the gut – tolerance to food protein can suppress immune response not only locally but body wide. We thus aimed to characterize the processes that enable to build up a body wide pool of ‘gut‐made’ regulatory T cells. These experiments had to deviate from the experimental work plan initially suggested because on the one hand side, we had to realize that in neonates T cells are largely absent from gut lamina propria and on the other hand the experimental approaches lacked sufficient resolution to track regulatory T cells disseminating from the gut. Thus, we established new experimental tools to tackle this question. We have generated a novel transgenic mouse model that allows for the sensitive tracking of regulatory T cell migration in vivo. We expect this model to be used in future experiments to pin point hot local interaction between T cells and macrophages in the gut lamina propria contribute to shape the body wide population of regulatory T cells.
Publications
- (2013). Antigen sampling in the small intestine. Trends Immunol 34, 155‐161
Schulz, O., and Pabst, O.
(See online at https://doi.org/10.1016/j.it.2012.09.006) - (2013). On the road to tolerance‐‐generation and migration of gut regulatory T cells. Eur J Immunol 43, 1422‐1425
Pabst, O., and Bernhardt, G.
(See online at https://doi.org/10.1002/eji.201243154) - (2013). Trafficking of regulatory T cells in the intestinal immune system. Int Immunol 25, 139‐143
Pabst, O.
(See online at https://doi.org/10.1093/intimm/dxs113) - (2014). Resident CD4+ T cells accumulate in lymphoid organs after prolonged antigen exposure. Nature communications 5, 4821
Ugur, M., Schulz, O., Menon, M.B., Krueger, A., and Pabst, O.
(See online at https://doi.org/10.1038/ncomms5821) - (2015). Active suppression of intestinal CD4(+)TCRalphabeta(+) T‐lymphocyte maturation during the postnatal period. Nature communications 6, 7725
Torow, N., Yu, K., Hassani, K., Freitag, J., Schulz, O., Basic, M., Brennecke, A., Sparwasser, T., Wagner, N., Bleich, A., et al.
(See online at https://doi.org/10.1038/ncomms8725) - (2015). Multicongenic fate mapping quantification of dynamics of thymus colonization. J Exp Med 212, 1589‐1601
Zietara, N., Lyszkiewicz, M., Puchalka, J., Witzlau, K., Reinhardt, A., Forster, R., Pabst, O., Prinz, I., and Krueger, A.
(See online at https://doi.org/10.1084/jem.20142143) - (2017). Tissue‐specific differentiation of colonic macrophages requires TGFbeta receptor‐mediated signaling. Mucosal Immunol 10, 1387‐1399
Schridde, A., Bain, C.C., Mayer, J.U., Montgomery, J., Pollet, E., Denecke, B., Milling, S.W.F., Jenkins, S.J., Dalod, M., Henri, S., et al.
(See online at https://doi.org/10.1038/mi.2016.142)
