Endoplasmic reticulum stress drives a regulatory phenotype in human T-cell clones.
T cells alter their functional phenotype during the evolution of an immune response (intra-lineage differentiation), but the driving forces to this plastic intra-lineage differentiation are poorly understood. The endoplasmic reticulum (ER) stress response is a possible critical event for the initial T cell differentiation upon antigen recognition. Here we studied the relationship between ER and Il-10 transcription in human Treg clones. The induction of ER stress with a canonical stressor, thapsigargin, enhances Il-10 transcription. Salubrinal, a small molecule inhibitor of the eukaryotic translation initiation factor 2α (eIF2α) dephosphporylation, dramatically inhibits it. Il-10 transcription is also enhanced by exogenous TNFα. These results disclose a role for ER stress in driving T cell plasticity.
Department of Pediatrics, Rady's Children's Hospital, University of California, San Diego, La Jolla, 92093-0641, United States. alfranco@ucsd.edu
Alessandra
A
Franco
Gonzalo
G
Almanza
Jane C
JC
Burns
Matthew
M
Wheeler
Maurizio
M
Zanetti
D000943:Antigens, Differentiation / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000276:immunology*; D002934:Cinnamates / Q000494:pharmacology; D002999:Clone Cells; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000276:immunology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000037:antagonists & inhibitors; D051858:Forkhead Transcription Factors / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000235:genetics; D009080:Mucocutaneous Lymph Node Syndrome / Q000276:immunology; D054645:Protein Phosphatase 1; D013312:Stress, Physiological / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000235:genetics
D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D002934:Cinnamates; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006360:Heat-Shock Proteins; C508609:IL10 protein, human; C508840:IL23A protein, human; D053760:Interleukin-23 Subunit p19; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C496827:salubrinal; D016753:Interleukin-10; D051742:Transcription Factor CHOP; D019284:Thapsigargin; D007371:Interferon-gamma; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1; D013890:Thiourea