Up-regulated expression of MICA on activated T lymphocytes involves Lck and Fyn kinases and signaling through MEK1/ERK, p38 MAP kinase, and calcineurin.
Major histocompatibility complex class I-related chain (MICA) is a cell stress-regulated molecule recognized by cytotoxic cells expressing the NKG2D molecule. MICA can be induced on T cells after CD3 or CD28 engagement. Here, we investigated the intracellular pathways leading to activation-induced expression of MICA. The Src kinase inhibitor PP1 inhibited up-regulated expression of MICA on anti-CD3-stimulated T cells. Downstream signaling routes involved mitogen-activated protein kinase (MAPK) kinase (MEK)1/extracellular signal-regulated kinase (ERK), p38 MAPK, and calcineurin, as MICA expression was prevented by U0126, SB202190, cyclosporin A, and FK506. Also, Lck and Fyn as well as MEK1/ERK and p38 MAPK were found to regulate MICA expression in anti-CD28/phorbol 12-myristate 13-acetate-stimulated T cells. Expression of MICA on activated T cells involved interleukin-2-dependent signaling routes triggered by Janus tyrosine kinases/signal transducer and activators of transcription and p70(S)(6) kinase, as it could be inhibited by AG490 and rapamycin. This is the first demonstration of the intracellular pathways involved in activation-induced expression of MICA, which may reveal potential targets for immune intervention to modulate MICA expression in pathological disorders.
Molinero
Luciana L
LL
Laboratorio de Inmunogenética, Hospital de Clínicas José de San Martín, Facultad de Medicina, Universidad de Buenos Aires, Argentina. nwz@sinectis.com.ar
Fuertes
Mercedes B
MB
Fainboim
Leonardo
L
Rabinovich
Gabriel A
GA
Zwirner
Norberto W
NW
D019703:Calcineurin / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors / Q000502:physiology; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D051076:Proto-Oncogene Proteins c-fyn; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D015395:Histocompatibility Antigens Class I; D007376:Interleukin-2; C099187:MHC class I-related chain A; D011518:Proto-Oncogene Proteins; C494957:FYN protein, human; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn; D017346:Protein Serine-Threonine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D019703:Calcineurin