The Rel/NF-κB pathway and transcription of immediate early genes in T cell activation are inhibited by microgravity

This study tested the hypothesis that transcription of immediate early genes is inhibited in T cells activated in mu g. 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 mu g 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 mu g from other variables of spaceflight. Microarray expression analysis after 1.5 h of activation demonstrated that mu g- and 1g-activated T cells had distinct patterns of global gene expression and identified 47 genes that were significantly, differentially down-regulated in mu g. Importantly, several key immediate early genes were inhibited in mu g. In particular, transactivation of Rel/NF-kappa B, 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 mu g and upon anti-CD3/anti-CD28 stimulation in simulated mu g. Analysis of gene connectivity indicated that the TNF pathway is a major early downstream effector pathway inhibited in mu g and may lead to ineffective proinflammatory host defenses against infectious pathogens during spaceflight. Results from these experiments indicate that mu g was the causative factor for impaired T cell activation during spaceflight by inhibiting transactivation of key immediate early genes. J. Leukoc. Biol. 92: 1133-1145; 2012.