Heat stress downregulates TCR zeta chain expression in human T lymphocytes.
After heat treatment, human T lymphocytes downregulate the T-cell receptor (TCR)/CD3-mediated [Ca(2+)](i) response and production of inositol triphosphate. Here we demonstrate that heat treatment of T lymphocytes at sublethal temperature decreases the expression of TCR zeta chain, which plays a critical role in the regulation of TCR/CD3-mediated signal transduction. Downregulation of TCR zeta chain in heat-treated T cells was observed at 8 h and reached a maximum at 16 h. Under these conditions, the expression of CD3 epsilon or TCR alphabeta chains was minimally affected. Consistent with the decrease in TCR zeta chain, a reduction in the level of TCR/CD3 induced tyrosine phosphorylation of several cellular protein substrates, and a delay in the kinetics of peak tyrosine phosphorylation was observed in heat-treated T cells. Interestingly, analysis of the TCR zeta chain content in the detergent-insoluble membrane fraction showed that heat treatment induces translocation of soluble TCR zeta chain to the cell membranes. In addition, the mRNA level of TCR zeta chain was reduced in heat-treated T cells. Correlative with the downregulation of TCR zeta chain mRNA, the level of the TCR zeta chain transcription factor Elf-1 was also reduced in heat-treated cells. We conclude that heat stress causes a decrease in the level of TCR zeta chain by increasing its association with the membranes and decreasing the transcription of the TCR zeta gene. Decreased expression of the TCR zeta chain is apparently responsible for the decreased TCR/CD3 responses of T cells.
Nambiar
M P
MP
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Fisher
C U
CU
Enyedy
E J
EJ
Warke
V G
VG
Krishnan
S
S
Tsokos
G C
GC
D000328:Adult; D015153:Blotting, Western; D017252:CD3 Complex / Q000096:biosynthesis / Q000235:genetics; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D015536:Down-Regulation; D005434:Flow Cytometry; D006358:Hot Temperature; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012995:Solubility; D013312:Stress, Physiological / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D017252:CD3 Complex; D004268:DNA-Binding Proteins; D003902:Detergents; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; C054979:antigen T cell receptor, zeta chain; D011505:Protein-Tyrosine Kinases