Mouse Antigen-Specific CD4+ T Cell Priming and Memory Response during Spaceflight (Mouse Immunology) - 12.07.16
The Mouse Antigen-Specific CD4+ T Cell Priming and Memory Response during Spaceflight (Mouse Immunology) investigation studies specific mechanisms of immune system activation, and whether immune system cells exposed to challenges before flight retain the "memory" to fight challenges during space flight. Space Explorers on future long-duration space missions may require preflight vaccinations or other precautions to prevent infection during space travel if immune memory is not retained. Science Results for Everyone
These mice get around. Tissues from space-flown mice contributed to several different studies. Results in this investigation showed suppressed immune function in real and simulated gravity, which indicates that simulated microgravity models can be used to develop baseline studies and augment experiments in true microgravity. Other data suggest the reduced mechanical load experienced in space may inhibit ability of bone and blood stem cells to regenerate and that microgravity induces changes in major salivary proteins that appear to diminish after longer exposure, meaning the changes may reflect adjustment to the space environment. Experiment Details
Millie Hughes-Fulford, Ph.D., University of California, San Francisco, CA, United States
Tammy T. Chang, Ph.D., M.D., University of California, San Francisco, San Francisco, CA, United States
Eduardo A. C Almeida, Ph.D., Moffett Field, CA, United States
David Fitzgerald, Ph.D., Oregon Health and Science University, Portland, OR, United States
Alan R. Hargens, Ph.D., University of California San Diego, San Diego, CA, United States
Larry F. Hoffman, Ph.D., University of California Los Angeles, Los Angeles, CA, United States
Maija Mednieks, Ph.D., University of Connecticut Health Center, Farmington, CT, United States
Joseph S. Tash, Ph.D., University of Kansas Medical Center, Kansas City, KS, United States
Stavros Thomopoulos, Ph.D., Washington University, St. Louis, MO, United States
Michael J. Pecaut, Ph.D., Loma Linda University, CA, United States
NASA Ames Research Center, Moffett Field, CA, United States
Sponsoring Space Agency
National Aeronautics and Space Administration (NASA)
Human Exploration and Operations Mission Directorate (HEOMD)
ISS Expedition Duration
March 2010 - September 2010
STS-131/19A is the first mission for Mouse Immunology.
- The Mouse Antigen-Specific CD4+ T Cell Priming and Memory Response during Spaceflight (Mouse Immunology) determines whether antigen-specific CD4+ T cell priming in vivo is inhibited or dysfunctional during space flight.
- This investigations will also determine whether antigen-specific CD4+ memory T cells are maintained normally during space flight and able to mount robust secondary responses.
- This investigation is important because space explorers on future long-duration missions beyond low Earth orbit may require vaccinations to prevent infection during space travel.
The Mouse Antigen-Specific CD4+ T Cell Priming and Memory Response during Spaceflight (Mouse Immunology) investigation determines whether immune responses can be initiated during space flight, and answers the question of whether memory CD4+ T cells (the mediators of immune protection after vaccinations are maintained and able to mount secondary responses. This is important issue because the immunity boost provided by vaccination is dependent upon the maintenance and function of memory T cells. Memory are functional differentiated, long-lived, and more resistant to apoptosis, controlled cell death. For this reason, they must be investigated in a separate set of experiments from normal T cells. Secondary immune responses mediated by memory cells are more rapid and efficient at clearing antigens and pathogens. Since immune protection by vaccines are mediated by memory T cells, deciphering whether memory responses are effective during space flight will determine whether preflight vaccinations may be useful countermeasures to future long-duration space explorers.
Once the samples are returned to Earth the PI utilizes standard laboratory techniques to determine the effects of microgravity on the immune system cells of the rodents.
This research is also expected to contribute data to the current body of research on microgravity effects on the skeletal, cardiovascular, and immune systems, liver and kidney function as well as other physiological systems through a tissue sharing program. Every effort will be made to harvest as many different samples and types of tissue from the mice as possible for other mission specific biomedical research. Positive results from this research may advance our understanding of mechanistic changes that occur in various physiological systems after exposure to microgravity and support overall efforts to reduce health risks to crewmembers. The investigations resulting from the Mouse Immunology tissue sharing program are as follows:
- Eduardo Almeida, Ph.D., Ames Research Center, Moffett Field, CA
Determine if the p53 signaling pathway, a key regulatory cell-signaling pathway, is responsible, for space-induced arrest of normal cell proliferation.
- Michael Delp, Ph.D., University of Florida, Gainesville, FL
To determine whether microgravity alters arterial vascular structure and key signaling pathways in cerebral arteries, the thoracic and abdominal aorta, mesenteric arteries, femoral arteries, and soleus and gastrocnemius muscle feed arteries.
- David Fitzgerald, Ph.D., Oregon Health and Science University, Portland, OR
To determine if the reduced biomechanical forces due to microgravity impair the ability of chondrocytes to maintain healthy articular cartilage, leading to increased cartilage breakdown.
- Alan R. Hargens, Ph.D., University of California San Diego, La Jolla CA
To determine if intervertebral disc morphology, cell content, swelling pressure, and glycosaminoglycan (GAG) and proteoglycan (PG) concentrations will significantly decrease following exposure to space flight.
- Larry Hoffman, Ph.D., University of California Los Angeles, Los Angeles, CA
Determine if Exposure to microgravity induces synaptic plasticity in the utriculi and sacculi which is manifested in an increase in the density of hair cell synaptic ribbons compared with Earth-gravity controls and determine if the readily releasable pool of vesicles at the active zone of utricular hair cell synapses are hemifused to the presynaptic membrane, and this pool of vesicles is labile to changes in the ambient gravitational environment.
- Maija Mednieks, Ph.D., University of Connecticut Health Center, Farmington, CT
Determine if extended weightlessness alters salivary glands and expression of their secretory protein.
- Joseph S. Tash, Ph.D., University of Kansas Medical Center, Kansas City, KS
To determine if exposure to microgravity disrupts normal estrous cycling, ovarian structure/function, and uterine horn morphology.
- Stavros Thomopoulos, Ph.D., Washington University, St. Louis, MO
To examine the effect of prolonged weightlessness on the biology of tendons and their insertions into bone.
Space flight immunosuppression is a significant obstacle to long-term human space travel. Of foremost concern is whether space travelers may be able to generate effective protective immune responses against infections while in space. Using an innovative mouse experimental model, this set of experiments will test whether initial specific activation of T cells is intact and whether memory T cell function is maintained during space flight.
Understanding the mechanisms of immune regulation is critical to the design of rational therapeutic interventions of these various disease processes. The immunosuppression observed during space flight provides important insight into the role of gravity in the generation of normal immune responses. Deciphering the mechanisms of space flight immunosuppression will provide a more complete picture of the important factors necessary for successful immune responses that may be masked in Earth-based experiments in the presence of gravity. These gravity-sensitive factors may hold the key to our ability to manipulate the immune system and develop therapeutic interventions that will treat the various disease processes affected by immunodysregulation. Dysregulated immune tolerance (overactive immune system) is linked to autoimmune diseases such as type I diabetes mellitus, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, and multiple sclerosis. On the other hand, many disease processes result from immunosuppression (underactive immune system).
Operational Requirements and Protocols
On orbit the mice AEM are relatively self-sufficient. The AEM contains enough food and water to house the mice safely and effectively for the mission duration. An astronaut will check the health status of the mice on a daily basis, by assessing them through the viewing window on the AEM.
Sixteen (16) mice are flown in the shuttle middeck housed in two animal enclosure modules (AEMs), 8 mice per each AEM. Half of the mice in both the group that flew to space and the group that stayed on Earth received transgenic thymus cells (T cells), a white blood cell and the immune system's first line of defense, which were exposed to a foreign protein, ovalbumin (OVA), challenge preflight and can retain the memory of how to rapidly respond to future OVA challenges. The other half of the mice were "naive," and their T cells were not exposed to a challenge until immediately after they returned from space. Flight and ground control mice are housed under the same environmental conditions (temperature, light/dark cycle, humidity, oxygen levels and carbon dioxide levels). All mice will receive the same full access to food and water. Upon return to Earth, the AEMs will be returned to the research team for analysis.
Decadal Survey Recommendations
Animal and Human Biology AH14
Animal and Human Biology AH15
It is known that gravity contributes to normal tissue growth and repair. The forces of gravity are absent during spaceflight, and therefore tissue stimulation is greatly diminished. Bone is a dynamic tissue that needs gravity for maintaining mineral content and structure. Bone health depends on a balance in the activities and signaling of various bone cells (osteoclasts, osteoblasts, and osteocytes), as well as growth of their parent stem cells. Research has found new evidence, for microgravity-induced osteocytic osteolysis (resorption of bone by osteocytes), and osteogenic cell cycle (bone building by osteoblasts) interruption in the active bone loss sites of the pelvic and femoral region of the mouse skeleton. Furthermore, cells isolated from the femoral head marrow compartment showed significant down-regulation of gene expression markers, demonstrating that microgravity is a strong inhibitor of tissue growth and regeneration mechanisms, acting at the level of early skeletal and blood stem cell differentiation (the process where stem cells mature into different specialized cells in the body). These results suggest that under conditions of reduced mechanical load, such as physical inactivity, mechanical disuse conditions, and spaceflight, it is likely that differentiation of somatic stem cells, such as in bone and blood, may be inhibited, impacting regenerative capacity (Blaber et al. 2013, 2014). Environmental sampling and cultures of the International Space Stations (ISS) show that numerous species of common Earth bacteria and fungi have hitchhiked to space through human skin, oral, and gastrointestinal flora, and this microbial contamination is increasing with time. Although it is possible that human space travelers may encounter alien microbes, a more likely scenario is that they would continue to come in contact with Earth-derived microorganisms to which their body has immunologic experience and established immune memory. But because of an impaired immune system associated with living in microgravity, easily treatable infections on Earth may turn into serious illness during prolonged spaceflight, such as on a voyage to Mars, or long stay on a space outpost. Research has found that spaceflight caused significant impairment in normal functions of T cells (a type of white blood cell essential for human immunity), maintenance of memory T-cell homeostasis, and led to the development of a heightened inflammatory response. This raises the possibility that humans who acquire an infection during long-term spaceflight may develop excessive inflammation and associated adverse tissue damage (Chang et al. 2015). Scientists also compared the effects of true microgravity (μg) on ISS and simulated microgravity (sμg), using the rotating wall vessel (RWV) and the random positioning machine (RPM), on the expression of key early T-cell activation genes in mouse splenocytes. Results demonstrate significantly increased gene expression in activated ground samples with suppression of mouse immune function in spaceflight, RPM and RWV samples. These findings indicate that sμg models provide an excellent test bed for scientists to develop baseline studies and augment true μg in spaceflight experiments (Martinez et al. 2015).^ back to top
Zhao L, Tanjung N, Swarnkar G, Ledet E, Yokota H. Regulation of eIF2α phosphorylation in hindlimb-unloaded and STS-135 space-flown mice. Advances in Space Research. 2012; 50(5): 576-583. DOI: 10.1016/j.asr.2012.05.024.
Blaber EA, Dvorochkin N, Lee C, Alwood JS, Yousuf R, Pianetta P, Globus RK, Burns BP, Almeida EA. Microgravity induces pelvic bone loss through osteoclastic activity, osteocytic osteolysis, and osteoblastic cell cycle inhibition by CDKN1a/p21. PLOS ONE. 2013 April 18; 8(4): e61372. DOI: 10.1371/journal.pone.0061372.
Chang TT, Spurlock SM, Candelario TT, Grenon SM, Hughes-Fulford M. Spaceflight impairs antigen-specific tolerance induction in vivo and increases inflammatory cytokines. FASEB: Federation of American Societies for Experimental Biology Journal. 2015 June 17; 29(10): 4122-4132. DOI: 10.1096/fj.15-275073. PMID: 26085131.
Martinez EM, Yoshida MC, Candelario TT, Hughes-Fulford M. Spaceflight and simulated microgravity cause a significant reduction of key gene expression in early T-cell activation. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. 2015 January 7; epub. DOI: 10.1152/ajpregu.00449.2014. PMID: 25568077.
Stabley JN, Dominguez, II JM, Dominguez CE, Mora Solis FR, Ahlgren J, Chapes SK, Muller-Delp JM, Pecaut MJ. Spaceflight Reduces Vasoconstrictor Responsiveness of Skeletal Muscle Resistance Arteries in Mice. Journal of Applied Physiology. 2012 11/01/2012; 113(9): 1439-1445. DOI: 10.1152/japplphysiol.00772.2012.
Blaber EA, Dvorochkin N, Torres ML, Yousuf R, Burns BP, Globus RK, Almeida EA. Mechanical unloading of bone in microgravity reduces mesenchymal and hematopoietic stem cell-mediated tissue regeneration. Stem Cell Research. 2014 September; 13(2): 181-201. DOI: 10.1016/j.scr.2014.05.005. PMID: 25011075.
Ground Based Results Publications
Hughes-Fulford M. The role of signaling pathways in osteoblast gravity perception. Journal of Gravitational Physiology. Journal of Gravitational Physiology. 2002; 9(1): 257-260.
Hatton JP, Gaubert F, Cazenave J, Schmitt D. Microgravity modifies protein kinase C isoform translocation in the human monocytic cell line U937 and human peripheral blood T-cells. Journal of Cellular Biochemistry. 2002; 87(1): 39-50.
Hughes-Fulford M, Rodenacker K, Jutting U. Reduction of anabolic signals and alteration of osteoblast nuclear morphology in microgravity. Journal of Cellular Biochemistry. 2006; 99: 435-449. DOI: 10.1002/jcb.20883.
Hughes-Fulford M. Physiological effects of microgravity on osteoblast morphology and cell biology. Advances in Space Biology and Medicine. 2002; 8: 129-157.
Hughes-Fulford M. Function of the cytoskeleton in gravisensing during spaceflight. Advances in Space Research. 2003; 32(8): 1585-93.
Boonyaratanakornkit JB, Cogoli A, Li CF, Schopper T, Pippia P, Galleri G, Meloni MA, Hughes-Fulford M. Key gravity-sensitive signaling pathways drive T cell activation. FASEB: Federation of American Societies for Experimental Biology Journal. 2005; 19(14): 2020-2.
Flight Systems Implementation
Image of the Animal Enclosure Module which will house the rodents used in the Mouse Immunology investigation. Image courtesy of Ames Research Center, Moffett Field, CA.
+ View Larger Image