Science for Health
28 June 2013
NIMR scientists have identified distinct miRNA-mediated molecular pathways that fine-tune regulatory T cells to control divergent inflammatory responses. The research is published in PLOS Pathogens.
Sometimes we need to keep our immune system in check. Failure to regulate the immune system, following infection or exposure to allergens, can result in devastating immunopathology with collateral tissue damage, organ dysfunction and death. Regulatory T cells (Treg cells), as their name suggests, counterbalance effector T cells thereby preventing excessive inflammation. Treg cell based therapies are being experimentally tested in the clinic as treatments for inflammatory diseases, such as autoimmunity and asthma. It remains unclear what kind of Treg cells would be most appropriate for a particular situation, given the diversity of effector immune responses. We want to know whether any Treg cell can suppress any immune response.
Mark Wilson (pictured) and his team in NIMR’s Division of Molecular Immunology approached this problem by asking fundamental questions relating to Treg cell biology and investigating whether differing inflammatory responses give rise to different Treg cells. Using four in vivo inflammatory disease models (chronic Schistosoma mansoni infection, chronic Leishmania major infection, acute Type-1- or Type-2- induced pulmonary inflammation) they discovered that Treg cells adopt distinct transcriptional identities in response to different inflammatory environments. Investigating the mechanistic pathways regulating the different Treg populations, they sequenced small RNA species and identified divergent miRNA profiles, reflecting the diverse transcriptional profiles. Applying novel in silico analyses with Monte Carlo simulations, they identified two master 'regulatory miRNAs', called miR-182 and miR-10a, that are regulated by distinct up-stream transcription factors that critically control Treg specialization, stability and function. This study indicates that Treg cells are heterogeneous and are shaped by the inflammatory environment they are targeted to control. It also shows that distinct miRNA pathways orchestrate fine-tuned programs for Treg suppressor function.
This study supports the notion that regulatory T cells may be as diverse as the effector responses they are programmed to suppress. We have identified that 'miRNA regulatory hubs', which function like transcription factors, fine-tune gene programs and are essential for regulatory T cell function. Whether these, or other, miRNAs can be used to reprogram or fine tune cells to generate different regulatory T cell populations for therapeutic use, is one potentially exciting future direction."
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Inflammatory signals (IL-4 or IL-12/IFNg), which drive effector T cells (Th2 and Th1, respectively), also trigger distinct miRNA profiles in regulatory T cells allowing them to better control the inflammatory response.
Samir Kelada, Praveen Sethupathy, Isobel S. Okoye, Eleni Kistasis, Stephanie Czieso, Sandra D. White, David Chou, Craig Martens, Stacy M. Ricklefs, Kimmo Virtaneva, Dan E. Sturdevant, Stephen F. Porcella, Yasmine Belkaid, Thomas A. Wynn, Mark S. Wilson (2013)
miR-182 and miR-10a Are Key Regulators of Treg Specialisation and Stability during Schistosome and Leishmania-associated Inflammation
PLOS Pathogens 9(6): e1003451. Article fulltext.
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