Tregs or regulatory T-cells that act as watchmen of the immune system often face harsh conditions such as starvation. To survive starvation and carry out their policing duties, Tregs need the protein Notch-1 to trigger a self-cannibalisation process at just the right time, show scientists from the Institute for Stem Cell Biology and Regenerative Medicine (inStem), Bangalore, and the National Centre for Biological Sciences.

Key words: Tregs, regulatory T-cells, surviving starvation, autophagy, immune regulation, autoimmunity, Notch-1 signalling

Sneezing, sniffling, watering eyes and achy fevers. It is that time of the year again when ‘flus, colds and allergies abound. During this time, our immune systems – the elite armies protecting us from invading germs – are at their busiest.

An important part of these armies consists of T-cells, so called because they mature in the organ known as the Thymus. In the event of an infection, T-cells divide rapidly to mount an immune response, but post-infection, this response must be shut down.

This winding-down process is accomplished by regulatory T-cells or Tregs. Tregs are also responsible for suppressing aberrant immune responses that attack a body’s own healthy cells and tissues. Tregs are essentially the watchmen of the immune system.

In a laboratory dish, a collection of Tregs are being starved. In about 6 hours, a process known as autophagy (auto – “self”, phagos – “eating”) sets in – the cells are beginning to cannibalise themselves to stay alive.

In their role as watchmen, Tregs often face harsh conditions such as starvation. For survival and continued function, these cells resort to autophagy, a highly regulated process that can recycle non-essential portions of a starving cell to generate energy.    

Scientists from the Institute for Stem Cell Biology and Regenerative Medicine (inStem), and the National Centre for Biological Sciences (NCBS), Bangalore, have identified a well-known signalling molecule – primarily involved in development – to be essential for autophagy onset in Tregs. Researchers have demonstrated that Tregs need the protein Notch-1 to trigger autophagy at just the right time to survive starvation and carry out their policing duties.

Notch-1 is a receptor on the outer membrane of cells and an important part of the Notch-signalling pathway involved in the development of T-cells. Notch-signalling also plays a role in other critical processes such as the formation of nerve cells, blood vessels, and the pancreas. Faulty notch-signalling is further implicated in many cancers, and diseases such as multiple sclerosis.

In Apurva Sarin’s laboratory at inStem, the role of Notch signalling in mammalian cells has been the subject of intense investigation. In a new study published in the journal eLife, Nimi Marcel from Sarin’s group outlines a distinctly different role for Notch-1 in mature Tregs – Notch-1 promotes survival during starvation.

“Until now, most work on Notch-1 focussed on how it regulates a cell’s fate – what a cell will develop into. The really unique part of our recent study is that we describe a post-developmental role for Notch-1 in mature cells,” says Marcel.

Using mice as a model system, Marcel and Sarin investigated Notch-1 mediated signalling in mature and starving Tregs. When Tregs isolated from mice are grown in petri plates and deprived of nutrition, Notch-1 is needed to trigger autophagy at the right time in the starving Tregs. Without the Notch-1 signalling, Tregs die under such conditions.

“Another distinctive result in our work is the connection that we establish between autophagy and Notch-1 signalling. Both are very old, evolutionarily conserved pathways, and to my knowledge, this is the first time a link has been found between the two,” says Marcel.

Further experiments have also found that the Notch-1 receptor is essential for Tregs to function properly in mice. Animals born lacking this receptor in Tregs quickly develop inflammations in response to even minor irritations. Such mice also showed signs of developing autoimmune disorders.   

Based on their observations on Tregs, Marcel and Sarin are also trying to see if the Notch-1 signalling and autophagy nexus exists in other cells. Future work is going to focus on trying to find the precise steps by which Notch-1 controls autophagy, as well as to investigate how wide-spread the phenomenon is.

“We would like to understand if these interactions are restricted to specialized cells of the immune system or describe broad principles that operate in a wider context,” explains Marcel.

About the paper:

The work described here was published in a paper titled “Notch1 regulated autophagy controls survival and suppressor activity of activated murine T-regulatory cells” in the journal eLife in June 2015. The paper can be accessed here: https://elifesciences.org/content/5/e14023

About the authors:

Nimi Marcel is affiliated to the Institute for Stem Cell Biology and Regenerative Medicine (inStem), Bangalore, and Manipal University, Manipal.

Apurva Sarin is affiliated to the National Centre for Biological Sciences (NCBS) and the Institute for Stem Cell Biology and Regenerative Medicine (inStem), Bangalore.

Contact:

Apurva Sarin is open to being contacted by email: sarina@ncbs.res.in

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The Bangalore Biocluster consists of the National Centre for Biological Sciences (NCBS), the Institute of Stem Cell Biology and Regenerative Medicine (inStem) and the Centre for Cellular and Molecular Platforms (CCAMP). Each of these institutions has its own scientific mandate, though all three share a common campus space that promotes synergistic associations between them. For more information, please visit: http://ncbs.res.in; http://instem.res.in; http://ccamp.res.in