IntroductionSpaceflight leads to the deconditioning of multiple body systems including the immune system. We sought to characterize the molecular response involved by capturing changes in leukocyte transcriptomes from astronauts transitioning to and from long-duration spaceflight.MethodsFourteen male and female astronauts with ~6-month- long missions aboard the International Space Station (ISS) had 10 blood samples collected throughout the three phases of the study: one pre-flight (PF), four in-flight (IF) while onboard the ISS, and five upon return to Earth (R). We measured gene expression through RNA sequencing of leukocytes and applied generalized linear modeling to assess differential expression across all 10 time points followed by the analysis of selected time points and functional enrichment of changing genes to identify shifts in biological processes.ResultsOur temporal analysis identified 276 differentially expressed transcripts grouped into two clusters (C) showing opposite profiles of expression with transitions to and from spaceflight: (C1) decrease-then-increase and (C2) increase-then-decrease. Both clusters converged toward average expression between ~2 and ~6 months in space. Further analysis of spaceflight transitions identified the decrease-then-increase pattern with most changes: 112 downregulated genes between PF and early spaceflight and 135 upregulated genes between late IF and R. Interestingly, 100 genes were both downregulated when reaching space and upregulated when landing on Earth. Functional enrichment at the transition to space related to immune suppression increased cell housekeeping functions and reduced cell proliferation. In contrast, egress to Earth is related to immune reactivation.ConclusionThe leukocytes’ transcriptome changes describe rapid adaptations in response to entering space followed by opposite changes upon returning to Earth. These results shed light on immune modulation in space and highlight the major adaptive changes in cellular activity engaged to adapt to extreme environments.