Key gravity‐sensitive signaling pathways drive T‐cell activation

Abstract

Returning astronauts have experienced altered immune function and increased vulnerability to infection during spaceflights dating back to Apollo and Skylab. Lack of immune response in microgravity occurs at the cellular level. We analyzed differential gene expression to find gravity-dependent genes and pathways. We found inhibited induction of 91 genes in the simulated freefall environment of the random positioning machine. Altered induction of 10 genes regulated by key signaling pathways was verified using real-time RT-PCR. We discovered that impaired induction of early genes regulated primarily by transcription factors NF-kappaB, CREB, ELK, AP-1, and STAT after crosslinking the T-cell receptor contributes to T-cell dysfunction in altered gravity environments. We have previously shown that PKA and PKC are key early regulators in T-cell activation. Since the majority of the genes were regulated by NF-kappaB, CREB, and AP-1, we studied the pathways that regulated these transcription factors. We found that the PKA pathway was down-regulated in vg. In contrast, PI3-K, PKC, and its upstream regulator pLAT were not significantly down-regulated by vectorless gravity. Since NF-kappaB, AP-1, and CREB are all regulated by PKA and are transcription factors predicted by microarray analysis to be involved in the altered gene expression in vectorless gravity, the data suggest that PKA is a key player in the loss of T-cell activation in altered gravity.

Gene Expression Microarrays in Microgravity Research: Toward the Identification of Major Space Genes

“…For this study they used Human Genome Focus Arrays (Affymetrix) and identified 91 down-regulated genes as a result of exposure to simulated microgravity. The expression of early genes regulated primarily by transcription factors NF-κB, CREB, ELK, AP-1, and STAT were impaired in microgravity, suggesting that microgravity either slows, impedes, or fully blocks key signaling pathways in early T cell activation (Boonyaratanakornkit et al, 2005). They showed that IL-2 was among the down-regulated genes, which correlates well with previous nonarray based reports (Cogoli et al, 1993;Pippia et al, 1996;Walther et al, 1998;HughesFulford et al, 2005).…”

Experimental design and environmental parameters affect Rhodospirillum rubrum S1H response to space flight

“…The RPM was operated as a random walk three-dimensional clinostat (basic mode) with an angular velocity of rotation of 60 deg s À1 (Walther et al, 1998) for 10 days (maximum cultivation time allowance for that facility). Random rotation at 60 deg s À1 , 1-10 cm away from the center of rotation, yields gravity contours from 1.12 Â 10 À3 to 1.12 Â 10 À2 g as calculated by g 0 ¼ (o 2 R)/g 0 , where o ¼ 1.05 radian s À1 , R ¼ 0.01-0.10 m and g 0 ¼ 9.81 m s À2 (Hoson et al, 1997;Boonyaratanakornkit et al, 2005).…”

Acclimation during space flight: effects on human physiology

“…Weightlessness may also contribute to flight-associated immune dysregulation. In-flight and ground-based studies have shown that the lack of gravity impedes signalling pathways essential for early T-cell activation 50 and leads to alterations in the organization of the cytoskeleton and microtubule organizing centres. 51,52 Potential adverse clinical events that may be related to prolonged dysregulation of the immune system include hypersensitivities, autoimmunity, allergies, infectious diseases, latent viral reactivation and even malignant diseases.…”