MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Allergies such as Atopic Dermatitis (AD) are rampant in the industrialized nations. Why are we more predisposed to developing hypersensitive reactions to innocuous proteins (allergens) is not well understood. To gain better understanding and to develop better therapies, we need to first delve deeper into how our immune system regulates homeostasis in tissues such as skin. The main cell types that thwart inflammatory reactions are known as regulatory T cells. These cells are generated in thymus and reside in secondary lymphoid tissues but they are also prominent at tissue sites such as in dermal layer of skin. In this study, I focused on understanding how Tregs resident in skin are distinct from the Tregs in secondary lymphoid organs such as lymph nodes (LNs). I uncovered that functioning of Tregs in skin is underpinned by a distinct set of genes. One main gene that I found to be highly expressed in skin Tregs but not in LN Tregs is Rora, which encodes for the transcription factor ROR alpha (RORa).
This observation was intriguing as previous studies had elucidated the requirement of RORa in the development of inflammatory type-2 innate lymphoid cells (ILC2s) and it has been considered the antagonizing RORa functioning would curb allergic responses. However, I observed that Tregs require RORa to suppress allergic responses. In particular, RORa regulates the expression of a TNF receptor family member DR3, which binds to the cytokine TL1A. TL1A has a role in enhancing suppressive activity of Tregs while also enhancing type-2 cytokine production from ILC2s. Hence, in the absence of DR3 in Tregs, we believe more TL1A is available to ILC2s resulting in unrestrained allergic responses.
MedicalResearch.com: What should readers take away from your report?
- Skin Tregs are distinct from Tregs in the LNs. A lot of studies focus on understanding the functions of immune cells by isolating cells from LNs and spleens, which are easy to work with. But a lot of the action happens in tissues. I was fascinated by the variety of immune cells that are constantly surveilling or are resident in skin. In fact, some the immune cells migrate to the skin during embryogenesis itself reinforcing the importance of these tissue resident cells in keeping us healthy. In this study, I focused on understanding the role of transcriptional regulator RORa, which I observed to be highly expressed in skin Tregs and found that while it is not required for the maintenance of Tregs in skin but the functioning of these cells is perturbed by its absence.
- Allergic reactions are heterogeneous. Often we club immune reactions in discrete categories. For e.g. it is though that in a type-2 reaction, IL-4, IL-5 and IL-13 cytokines are secreted together in similar amounts by type-2 lymphocytes. In this work, I observed that upon treatment of mice with MC903 (an allergy inducing compound) eosinophilia was dramatically increased in the absence of RORa in Tregs. The increase in eosinophilia was associated with an increase in cytokine IL-5 and chemokine Ccl8. Other cytokines such as IL-4 and IL-13 were modestly increased as was the infiltration of other granulocytes. Why more IL-5 and infiltration of eosinophils and not as many mast cells or basophils is intriguing and sheds light on the complex finely regulated gene network that we are gradually uncovering by analyzing data at single cell level.
- Tissue Tregs resident in barrier sites such as gut and skin have unique developmental requirements. It has been shown that Tregs are prevalent in colonic lamina propria, where they are induced by microbial stimuli and short chain fatty acids. These Tregs help in suppressing food allergies and have been shown to depend on transcription factor RORg Interestingly, we observed that unlike colonic Tregs, Tregs in skin are largely of thymic origin and express RORa but not RORgt. These findings illustrate that both of these barrier sites rely on Tregs for suppression of allergic responses but utilize different ROR family members.
- Blocking TL1A as a therapy for atopic dermatitis. While the importance of RORa in the immune system had been well established, its role in Tregs and the genes it regulates in Tregs had not been known. One major gene that I observed to be affected in Tregs in the absence of RORa is DR3, a receptor of TNF receptor family. This receptor is activated by the binding of TL1A cytokine, which is released by epithelial or endothelial cells. Interestingly, blocking TL1A attenuates inflammatory responses in asthma and inflammatory bowel disease. Hence, biologics are being generated by pharmaceuticals like Pfizer and Teva to block TL1A mediated inflammation. This study is first in my knowledge to suggest the role of TL1A in also mediating skin allergic eosinophilic reactions and its connection to RORa in Tregs.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Publishing scientific stories often focus on the findings that connect well. But, in the process of generating a story, a lot of data is generated. In this study, we uncovered many genes that were downregulated in the absence of RORa in Tregs. Some of them were involved in adenosine pathway, which is necessary for metabolism and immunosuppression. Other genes that were also affected are circadian rhythm regulators. In my view, a more deeper understanding of how these genes and pathways fine- tune the functioning of skin Tregs would be very exciting for future research. Further, we observed that Tregs in the dermis are constantly moving very close to blood vessels. Why are these cells surveilling in proximity to vasculature is yet to be understood. Also, as a trained developmental immunologist during my PhD, I would be very interested in understanding the progenitors of Tregs that traffic to skin. Tregs are known to traffic in neonatal period to the skin. Is RORa and some of these genes upregulated in thymic Tregs selected to see skin specific antigens would be an exciting area of future research.
Last, how can we translate these basic findings into therapies. Could blocking TL1A be used for AD or other eosinophilic dominant inflammation such as Eosinophilic esophagitis remains to be known.
MedicalResearch.com: Is there anything else you would like to add?
Response: For this work, I feel fortunate to have the financial support in Geha lab to hypothesize, and generate most of the results before leaving for my current position as a senior scientist at Elstar Therapeutics. I am thankful in particular to my collaborators: Dr.Olga Barriero and Dr. Unmesh Jhadav for helping me with the generation of vital pieces of data for these studies. I have no disclosures.
Nidhi Malhotra, Juan Manuel Leyva-Castillo, Unmesh Jadhav, Olga Barreiro, Christy Kam, Nicholas K. O’Neill, Francoise Meylan, Pierre Chambon, Ulrich H. von Andrian, Richard M. Siegel, Eddie C. Wang, Ramesh Shivdasani, Raif S. Geha. RORα-expressing T regulatory cells restrain allergic skin inflammation. Science Immunology, 2018; 3 (21): eaao6923 DOI: 10.1126/sciimmunol.aao6923
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