Role of Interleukin-2 Receptor in Signal Transduction and Gravisensing Threshold of T-Lymphocytes-2 (Leukin-2) - 02.08.17
Leukin-2 will study the signal transduction pathway of the activation of T-lymphocytes. This investigation will also determine if loss of Interleukin-2 receptor expression is the cause of inhibition. Microgravity will be used as an inhibitor of activation. Science Results for Everyone
Microgravity suppresses T-cells, which are white blood cells that fight infections. This experiment indicates microgravity actually inhibits T-cell activation genes and is the first to report that spaceflight affects expression of microRNA – small, non-coding RNA molecules. Previous studies showed increased microRNA activity after T-cell activation, suggesting these molecules are how gravity regulates T-cell activation. At least one key microRNA, miR-21, showed reduced expression in true microgravity, indicating that microgravity represses immune genes. This previously unknown immune response control, termed self-limiting induction, may apply to other normally self-limiting growth such as wound healing and its malfunction may cause cancer. Experiment Details
Isabelle Walther, Ph.D., Swiss Federal Institute of Technology, Space Biology, Zurich, Switzerland
Augusto Cogoli, Ph.D., Zero-g Tec GmbH, Zurich, Switzerland
Millie Hughes-Fulford, Ph.D., University of California, San Francisco, CA, United States
Proto Pippia, Universiy of Sassari, Sassari, Italy
Swiss Federal Institute of Technology, Space Biology, Zurich, Switzerland
Sponsoring Space Agency
European Space Agency (ESA)
ISS Expedition Duration
September 2006 - April 2007
A previous Leukin investigation was flown on STS-107 (Columbia) in 2003. This investigation will fly again for ESA on Expedition 14.
- Leukin-2 will help investigators understand why single cells are sensitive to microgravity and to study the microgravity effect on the immune system cells.
- The results of Leukin-2 will enable understanding of the cause of reduced immune function associated with spaceflight so crew members stationed on the Moon or on a Mars mission will remain healthy.
The International Space Station provides a modern platform to study physiology and molecular changes in space. In addition, understanding these physiological changes provides knowledge that we can apply to common diseases found in the general population. The results also help us to understand microgravity-induced immunosuppression.
Early NASA studies demonstrated that the lymphocytes (white blood cells) had a decreased response to mitogen stimulation of growth. In the late 60's returning Apollo astronauts were found to have reduced immune function after spaceflight, taking approximately 7 days to recover normal function. Astronauts exposed to microgravity did not respond to mitogen, a protein that encourages cell division, while cells belonging to non-flown astronaut backups had normal response.
The aim of Leukin-2 is to study the signals which cause the activation of T-lymphocytes, white blood cells that play a central role in cell-mediated immunity. The focus is on the role of Interleukin-2 (IL-2), a hormone that stimulates the growth of T-lymphocytes and plays an instrumental role in the body's response to pathogens (bacteria, viruses, fungi, etc.) and in the determination of its genetic expression (process by which a gene's DNA sequence is converted into the structures and functions of a cell).
Leukin-2 may help scientists to better understand the depression of the immune system which occurs during spaceflight and, therefore, to devise more adequate preventive or corrective measures for crew members during long duration missions.
Determining the factors which cause IL-2 suppression can help scientists on Earth better treat immunosuppressed patients.
Operational Requirements and Protocols
The T-lymphocytes will be purified and sealed in experiment containers shortly before launch. Once on orbit an astronaut will inject an activator. After intervals of 0 minutes, 30 minutes and 4 hours the cultures will be fixed, by injection of a preservation solution, frozen and returned to the investigators for analysis.
Decadal Survey Recommendations
Information Pending^ back to top
Immunosuppression during spaceflight could be a major barrier to safe, long-term human space travel. Research has shown that the immune system is compromised by weightlessness and the lack of immune response during spaceflight occurs at the cellular level. T cells, or T lymphocytes (a type of white blood cells produced by the thymus gland to fight infections), interact with many different cell types, and are able to ‘remember’ specific pathogens. Activation of T-cells can lead to a number of immune responses such as antibody production, mobilization of phagocytic cells, and direct killing of infected cells. Previous in-vitro laboratory studies demonstrated that T-cell activation was suppressed by microgravity, independent of other systemic factors. The goals of flight experiments are to show that actual spaceflight can impair T cell activation, as well as understand the mechanisms controlling early activation of T-cells. Results from the International Space Station (ISS) indicate that microgravity disrupts activation transcription proteins involved in the process of converting DNA into RNA and significantly inhibits several key immediate early T-cell activation genes. Global microarray analysis revealed significant suppression of 85 genes under microgravity conditions compared to gene up-regulation in onboard normal gravity-activated samples. Gene connectivity analysis indicated that a cell signaling protein, tumor necrosis factor (TNF), involved in systemic inflammation pathway, is a major early downstream effector pathway inhibited in microgravity and may lead to ineffective pro-inflammatory host defenses against infectious pathogens during spaceflight. It appears that gravity regulates early T-cell activation not only by transcription promotion but also, interestingly, by blocking protein synthesis with microRNAs. A microRNA (abbreviated miRNA) is a small non-coding RNA molecule that functions in RNA silencing and post-transcriptional regulation of gene expression. Previous studies have shown that key miRNAs are up regulated after activation of human T cells. Data from ISS showed that 1 miRNA (miR-21 which plays a crucial role in many cellular functions and diseases including cancer and cardiovascular diseases) had reduced gene expression in true microgravity. In normal gravity, miR-21 was increased 2-fold, while in microgravity miR-21 was not significantly changed demonstrating an altered profile of miRNA expression when compared to onboard normal gravity controls. Of interest, samples from onboard 0.5g samples demonstrated that fractional gravity is capable of restoring gene expression of miR-21. Several miR-21 targets are co-up-regulated with miR-21 during early activation suggests that miR-21 may be involved in a previously unrecognized auto regulatory loop that limits the duration of normal T-cell activation. Moreover, this study suggests that T-cell activation itself may induce a sequence of gene expressions that is self-limited by miR-21. This is the first time that miRNAs have been analyzed using an onboard normal gravity control centrifuge eliminating possible confounders such as launch effects, cosmic radiation, and vibration, leaving only gravity conditions as a variable. Together, these microgravity experiments support the hypothesis of miR-21 translational repression of key immune genes. This previously unknown mechanism controlling the immune response has been termed self-limiting induction. This mechanism may apply to other growth induction that is normally self-limiting, such as wound healing. It is possible that in some tissues, dysfunction of this type of mechanism could lead to uncontrolled growth and result in cancer.^ back to top
Hughes-Fulford M, Chang TT, Martinez EM, Li C. Spaceflight alters expression of microRNA during T-cell activation. FASEB: Federation of American Societies for Experimental Biology Journal. 2015 August 14; epub. DOI: 10.1096/fj.15-277392. PMID: 26276131.
Chang TT, Walther I, Li C, Boonyaratanakornkit JB, Galleri G, Meloni MA, Pippia P, Cogoli A, Hughes-Fulford M. The Rel/NF-κB pathway and transcription of immediate early genes in T cell activation are inhibited by microgravity. Journal of Leukocyte Biology. 2012; 92(6): 1133-1145. DOI: 10.1189/jlb.0312157. PMID: 22750545.
Ground Based Results Publications
Sonnenfeld G. Editorial: Space flight modifies T cell activation--role of microgravity. Journal of Leukocyte Biology. 2012 December 1; 92(6): 1125-1126. DOI: 10.1189/jlb.0612314.
The information provided is courtesy of the ESA Astrolab Mission web page.
The Lab of Cell Growth - University of California Medical School, San Fancisco, CA