November 2017 NUI Galway Research Demonstrates the Importance of Sugar Molecules in Regulating Immune Responses

Research will help to understand the mechanisms of immune regulation and contribute to the development of new treatment strategies for autoimmune diseases such as multiple sclerosis and rejection of transplants

Researchers from NUI Galway’s Regenerative Medicine Institute (REMEDI) and Advanced Glycoscience Research Cluster (AGRC) have been working together to examine how sugar (carbohydrate) molecules attached to the surfaces of immune cells participate in the normal protective functions of those cells. The researchers have published two new studies in the leading open access journal Frontiers of Immunology, which demonstrate that chains of sugar molecules, referred to as glycans, attached to proteins and other components of the cell surface, play an essential role in the function of two very important cells of the immune system.

In the first study, PhD student Joana Cabral with Professor Matthew Griffin at REMEDI and Professor Lokesh Joshi at AGRC in NUI Galway, discovered that a specialised type of immune cell, the regulatory T cell (or T-reg), has a distinctive pattern of glycans on its surface compared to other T cell types. T-regs are known to play a policing role in the immune system that prevents inappropriate activation that can lead to autoimmune diseases such as multiple sclerosis and juvenile diabetes or to rejection of transplants. By using enzymes to ‘trim away’ the sugar molecules from the surface of T-regs, the research team, in collaboration with Dr Jared Gerlach of AGRC, observed that the ability of T-regs to suppress strong immune activity was heavily dependent on their normal glycan pattern. Insights from the research help to better understand the mechanisms of immune regulation and can contribute to the development of new treatment strategies for a range of diseases that involve over- or under-activity of the immune system.

In the second study, PhD student Kevin Lynch, working with Professor Thomas Ritter and Dr Aideen Ryan from REMEDI and Professor Lokesh Joshi investigated how a commonly used steroid medication alters the pattern of sugar molecules on immune cells known as dendritic cells (or DCs). The main function of DCs is to stimulate T-cells to act against foreign molecules (antigens) associated with infectious microbes or, alternatively, to prevent T-cells being activated against harmless antigens, a process known as immune tolerance. The research team found that after steroid treatment, DCs develop an increase in specific surface glycans that make them more likely to cause immune tolerance, a finding that may help to design new treatment approaches to prevent or treat autoimmune diseases and rejection of transplants. The group also found that when the same sugar molecules are removed from the surface of DCs, they become more powerful at stimulating active immune responses. This insight may be of particular relevance to cancer treatments which aim to increase T cell activation against antigens contained in tumours.

Commenting on the publication of the studies, Professor Matthew Griffin at NUI Galway, said: “The fascinating results we observed by manipulating the surface glycan patterns of T-reg are a beautiful example of the complexity of molecular interactions between different cells of the immune system. The work could not have been successful without a close collaboration between researchers from two very different disciplines. These collaborations have been built, in particular, on NUI Galway’s investment in infrastructure for Biomedical research and on Science Foundation Ireland’s funding support for research clusters in regenerative medicine and glycoscience and, more recently, the CÚRAM centre for research in medical devices.”

Professor Thomas Ritter at NUI Galway, commented: “These results could have important implications for both the field of immunotherapies and cancer treatment. The importance of sugar residues in controlling how immune responses occur is under-studied and warrants further investigations.”

Professor Lokesh Joshi, Vice President for Research at NUI Galway, said: “In contrast to the current state of gene and protein biology, many of the details of sugar-based structure and function throughout biology remain mysterious. The results of these studies underscore the importance of understanding complex glycans and their specific cues within the larger mechanisms of cellular interaction. This work provides new avenues for potentially enhancing or regulating elements of immune function. These findings could only have been made possible through collaboration with Professors Ritter and Griffin and the persistence of our respective research teams, all made possible by Ireland’s continuing support of high quality scientific research.”

Professor Michael O’Dwyer, Consultant Haematologist at NUI Galway and Galway University Hospital, and an internationally recognised expert in blood cancers, commented: “I am very excited about these results regarding the restoration to immunity after removal of sugar residues on antigen-presenting cells. I am currently working with Professor Ritter and Dr Ryan to investigate the role of glycans in the immune response to blood cancer. The exciting findings of this work, which show that the manipulation of sugar residues on stem cells helps to restore anti-cancer immune response, will be presented later this month at the annual meeting of the American Haematology Society.”

The research studies were supported by individual and centre grants from Science Foundation Ireland as well as a PhD fellowship to Dr Cabral through the Irish Government’s PRTLI5 initiative.

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