Beyond Th1 and Treg : intestinal T helper cells in disease and tolerance

The human intestinal tract is not only one of the largest organs by surface area in our bodies but also harbors the greatest number of immune cells. These cells are crucial for maintaining tolerance towards the various food and microbial antigens and mounting protective inflammatory responses towards invading pathogens. Inasmuch, a delicate balance exists between anti- and pro-inflammatory signals which are influenced by several factors and must remain in check to ensure appropriate responses towards innocuous and harmful stimuli. To this end, CD4+ T helper (Th) cells play a crucial role in orchestrating both tolerogenic and proinflammatory responses. This thesis sought to better understand the factors controlling Th cells in the context of different intestinal challenges.

In Studies I and II, we investigated how dietary cholesterol sensing can influence Th phenotypes during homeostasis. In Study I, we found that the liver X receptors (LXRs)— which senses oxidized forms of cholesterol—influence the balance of Foxp3+RORgt+ regulatory T cells (RORgt+ Tregs) and Foxp3-RORgt+ Th17 cells in the gut-draining mesenteric lymph nodes (MLNs). Differences in the microbiota could explain the changes in Th17 frequencies but not RORgt+ Tregs. Instead, we found that LXR signaling in CD11c+ cells altered the RORgt+ Treg population. In Study II, we found that ingestion of the LXR agonist GW3965 led to changes in the frequencies in the IL-10+ Foxp3+ Treg populations in the small intestine and spleen. Interestingly, while GW3965 led to a decrease in IL-10+ Tregs the small intestine, it decreased their frequency in the spleen. Intriguingly, mice lacking LXR signaling in CD11c+ cells failed to develop oral tolerance. Together, these studies demonstrate the importance of cholesterol sensing during steady state.

In Study III, we tracked the activation of naïve Th cells recognizing the commensal CBir1 antigen (CBir1 cells). We found that naïve CBir1 cells could be activated in the MLNs following dextran sulfate sodium (DSS)-induced colitis and that, once activated, they were preferentially skewed towards an effector rather than regulatory T cell phenotype which was plastic over time. Furthermore, while CBir1 cells were not pathogenic on their own, they led to increased disease score in a T cell-driven mouse model of colitis.

In Study IV, we analyzed how infection with the strictly enteric helminth Heligmosomoides polygyrus bakeri (H. polygyrus) could influence Th cell populations in the skin. H. polygyrus infection led to an increase in the number of Th cells in the skin. Interestingly, this was not due to translocation of bacteria or general intestinal inflammation. Instead, H. polygyrus infection led to an increase in MLN Th cells expressing the skin-homing receptors CCR4 and CCR10.

Taken together, the results in this thesis highlight the importance of cholesterol sensing and intestinal inflammation in controlling the fate of CD4+ Th cells in the gut and beyond.

List of scientific papers

I. Sara M. Parigi, Srustidhar Das, Annika Frede, Rebeca F. Cardoso, Kumar P. Tripathi, Cristian Doñas, Yue O. O. Hu, Per Antonson, Lars Engstrand, JanÅke Gustafsson and Eduardo J. Villablanca. Liver X receptor regulates Th17 and RORgt+ Treg cells by distinct mechanisms. Mucosal Immunology. 2021 Mar;14(2):411-419.
https://doi.org/10.1038/s41385-020-0323-5

II. Rebeca F. Cardoso, Annika Frede, Xinxin Luo, Srustidhar Das, Sterre Erades, Sara M. Parigi, Sterre Erades, Matteo Pedrelli, Paolo Parini and Eduardo J. Villablanca. Liver X receptor signaling in CD11c+ cells is necessary for the development of oral tolerance. [Manuscript]

III. Chiara Sorini*, Rebeca F. Cardoso*, Kumar P. Tripathi, Paulo Czarnewski, Oscar E. Diaz, Yael Holender, Charles O. Elson, Nicola Gagliani and Eduardo J. Villablanca. Intestinal damage promotes the differentiation of pathogenic commensal-specific T cells. *Contributed equally. [Manuscript]

IV. Cajsa H. Classon, Muzhen Li, Ada Lerma Clavero, Junjie Ma, Xiaogang Feng, Christopher A. Tibbitt, Julian M. Stark, Rebeca Cardoso, Emma Ringqvist, Louis Boon, Eduardo J. Villablanca, Antonio Gigliotti Rothfuchs, Liv Eidsmo, Jonathan M. Coquet & Susanne Nylén. Intestinal helminth infection transforms the CD4+ T cell composition of the skin. Mucosal Immunology. 2022 Feb;15(2):257-267.
https://doi.org/10.1038/s41385-021-00473-9