Key gravity-sensitive signaling pathways drive T cell activation.
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.
Boonyaratanakornkit
J B
JB
Lab of Cell Growth, Veteran's Affairs Medical Center, San Francisco, California 94121, USA.
Cogoli
A
A
Li
C-F
CF
Schopper
T
T
Pippia
P
P
Galleri
G
G
Meloni
M A
MA
Hughes-Fulford
M
M
D018480:Astronauts; D016000:Cluster Analysis; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015536:Down-Regulation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006112:Gravitation; D006801:Humans; D007107:Immune System; D008213:Lymphocyte Activation; D008954:Models, Biological; D015233:Models, Statistical; D016328:NF-kappa B / Q000096:biosynthesis; D020411:Oligonucleotide Array Sequence Analysis; D011493:Protein Kinase C / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000096:biosynthesis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000096:biosynthesis; D050807:ets-Domain Protein Elk-1 / Q000096:biosynthesis
D017362:Cyclic AMP Response Element-Binding Protein; D016328:NF-kappa B; D050791:STAT Transcription Factors; D018808:Transcription Factor AP-1; D050807:ets-Domain Protein Elk-1; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C