The findings, reported this week online in Nature Immunology, may lead to new therapeutic strategies for optimising effective immune responses against infections and disease.
The immune response triggered by these ‘killer T cells’ as they are known, is critical for the body to seek and destroy cancer cells, or cells infected by invading pathogens like bacteria and viruses. However, regulating the intensity of CD8+ T cell responses is also important to minimise tissue damage arising from their unrestrained activity. This new collaborative study between the groups of Dr Martin Turner from the Laboratory of Lymphocyte Signalling and Development at the Babraham Institute, Professor JohnWherry of the Department of Microbiology, University of Pennsylvania and Professor Peter Katsikis of the Department of Microbiology and Immunology at Drexel University in Philadelphia provides new insight into how the responses of CD8+ T cells are controlled.
The lynchpin in both generating an appropriate immune response and retaining immunological memory appears to be MicroRNA-155. These miniscule microRNA molecules are copied from DNA but do not encode proteins. They control gene activity by binding to specific related sequences, thereby interfering with a gene's ability to produce the proteins that co-ordinate cellular activities.
When CD8+ T cells are activated in response to pathogenic signals the level of MicroRNA-155 rises. Amongst the genes specifically targeted by MicroRNA-155 in CD8+ T cells are those regulating sensitivity to type I interferons - proteins made by the body in response to the presence of pathogens or tumour cells. Interferons belong to a large family of glycoproteins called cytokines, which act as cellular messengers to initiate the protective defences of the immune system, increasing recognition of infection and protecting cells from viral infections but they can also put a brake on T cells’ activity.
Dr Martin Turner, Head of Babraham’s Lymphocyte Signalling & Development Programme explained, “This transatlantic collaboration demonstrates the pivotal role that microRNAs play in governing how the immune system works and generating optimal immune responses by the CD8+ T cells. CD8+ T cells that lacked MicroRNA-155 were unable to mount a strong protective response and were more susceptible to the anti-proliferative effect of type I interferons. However, CD8+ T cells that overproduced MicroRNA-155, showed an increased immune response, following infection by the influenza virus. We were also surprised to find that the targets in CD8 T cells were not the same as in closely related CD4+ T cells.”
The research sheds light on an unresolved paradox regarding the role of type I interferon signalling in CD8+ T cell responses. Importantly, type I interferon provides a critical co-stimulatory signal for CD8+ T cell activation, but excessive type I interferon signalling mediates an anti-proliferative effect. The study thus identifies a previously unknown role for MicroRNA-155 in regulating responsiveness to interferon by tipping the balance in favour of CD8+ T cell activation.
Dr Peter Katsikis, senior author of the paper commented, “Being able to improve the CD8+ T cell response is a very exciting prospect. By overexpressing MicroRNA-155 in CD8+ T cells one could potentially make cells that fight off cancer and infections more efficiently.”
The Babraham Institute, which receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC), is a world-leading centre for studying the basic biology of signalling processes inside and between cells and bioscience underpinning health, supporting BBSRC’s mission to drive advances in fundamental bioscience for better health and improved quality of life.
Professor Michael Wakelam, Babraham’s Director said, “A key focus of our research is to understand the basic biology of signalling inside and between cells, particularly during ageing, and to determine how the body manages microbial and viral interactions. These new insights, revealing the intricate involvement of MicroRNAs in the regulation of the immune system, could point to future therapeutic targets and mechanisms to more efficiently harness components of our immune system to combat infection.”
Publication details:
MicroRNA-155 controls CD8+ T cell responses by regulating interferon signalling.
Donald T Gracias, Erietta Stelekati, Jennifer L Hope, Alina C Boesteanu, Travis A Doering, Jillian Norton, Yvonne M Mueller, Joseph A Fraietta, E John Wherry, Martin Turner & Peter D Katsikis
Nature Immunology (2013) http://dx.doi.org/10.1038/ni.2576
The Babraham Institute, which receives strategic funding (a total of £36.2M in 2011-12) from the Biotechnology and Biological Sciences Research Council (BBSRC), undertakes international quality life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. The Institute’s research provides greater understanding of the biological events that underlie the normal functions of cells and the implication of failure or abnormalities in these processes. Research focuses on signalling and genome regulation, particularly the interplay between the two and how epigenetic signals can influence important physiological adaptations during the lifespan of an organism. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and healthier ageing. (www.babraham.ac.uk)
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