This study tested the hypothesis that transcription of immediate early genes is inhibited in T cells activated in μg. Immunosuppression during spaceflight is a major barrier to safe, long-term human space habitation and travel. The goals of these experiments were to prove that μg was the cause of impaired T cell activation during spaceflight, as well as understand the mechanisms controlling early T cell activation. T cells from four human donors were stimulated with Con A and anti-CD28 on board the ISS. An on-board centrifuge was used to generate a 1g simultaneous control to isolate the effects of μg from other variables of spaceflight. Microarray expression analysis after 1.5 h of activation demonstrated that μg- and 1g-activated T cells had distinct patterns of global gene expression and identified 47 genes that were significantly, differentially down-regulated in μg. Importantly, several key immediate early genes were inhibited in μg. In particular, transactivation of Rel/NF-κB, CREB, and SRF gene targets were down-regulated. Expression of cREL gene targets were significantly inhibited, and transcription of cREL itself was reduced significantly in μg and upon anti-CD3/anti-CD28 stimulation in simulated μg. Analysis of gene connectivity indicated that the TNF pathway is a major early downstream effector pathway inhibited in μg and may lead to ineffective proinflammatory host defenses against infectious pathogens during spaceflight. Results from these experiments indicate that μg was the causative factor for impaired T cell activation during spaceflight by inhibiting transactivation of key immediate early genes.
Experiments conducted in space in the last two decades have shown that T lymphocyte activation in vitro is remarkably reduced in microgravity. The data indicate that a failure of the expression of the interleukin-2 receptor (measured as protein secreted in the supernatant) is responsible of the loss of activity. To test such hypothesis we have studied the genetic expression of interleukin-2 and of its receptor in concanavalin Aactivated lymphocytes with the RT-PCR technology. Microgravity conditions were simulated in the fast rotating clinostat and in the random positioning machine. The latter is an instrument introduced recently to study gravitational effects on single cells. Our data clearly show that the expression of both IL-2 and IL-2RK K genes is significantly inhibited in simulated 0Ug. Thus full activation is prevented.z 1998 Federation of European Biochemical Societies.
Certain functions of immune cells in returning astronauts are known to be altered. A dramatic depression of the mitogenic in vitro activation of human lymphocytes was observed in low gravity. T-cell activation requires the interaction of different type of immune cells as T-lymphocytes and monocytes. Cell motility based on a continuous rearrangement of the cytoskeletal network within the cell is essential for cell-cell contacts. In this investigation on the International Space Station we studied the influence of low gravity on different cytoskeletal structures in adherent monocytes and their ability to migrate. J-111 monocytes were incubated on a colloid gold substrate attached to a cover slide. Migrating cells removed the colloid gold, leaving a track recording cell motility. A severe reduction of the motility of J-111 cells was found in low gravity compared to 1g in-flight and ground controls. Cell shape appeared more contracted, whereas the control cells showed the typical morphology of migrating monocytes, i.e., elongated and with pseudopodia. A qualitative and quantitative analysis of the structures of F-actin, β-tubulin and vinculin revealed that exposure of J-111 cells to low gravity affected the distribution of the different filaments and significantly reduced the fluorescence intensity of F-actin fibers. Cell motility relies on an intact structure of different cytoskeletal elements. The highly reduced motility of monocytes in low gravity must be attributed to the observed severe disruption of the cytoskeletal structures and may be one of the reasons for the dramatic depression of the in vitro activation of human lymphocytes.
Summary. Investigations performed in space have shown that gravity changes affect important cellular mechanisms like proliferation, differentiation, genetic expression, cytoskeletal architecture, and motility in lymphocytes, monocytes, and other mammalian cells. In particular, a dramatic depression of the mitogenic in vitro activation of human peripheral blood lymphocytes was observed at low gravity. The hypothesis of the present work is that a reduced interaction between T lymphocytes and monocytes, essential for the second signalling pathway, might be one of the reasons for the observed depression of the in vitro activation of human lymphocytes. Cell motility and with it a continuous rearrangement of the cytoskeletal network within the cell is essential for cell-tocell contacts. Whereas nonactivated lymphocytes in suspension are highly motile at low gravity, no data are available so far on the motility of adherent monocytes. It thus can be argued that impaired monocyte locomotion and cytoskeletal changes could be responsible for a reduced interaction of monocytes with T lymphocytes. In this study, the locomotion ability of J-111 cells, an adherent monocyte cell line, attached to colloidal gold particles on coverslips and exposed to modelled low gravity in the random positioning machine was found to be severely reduced compared with that of controls and the structures of actin, tubulin, and vinculin were affected.
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