Phosphatidylinositol 4,5‐bisphosphate hydrolysis accompanies T cell receptor‐induced apoptosis of murine thymocytes within the thymus

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@article{18b2fff4ce7c4ee9bd1b3acf853107c2,
title = "Phosphatidylinositol 4,5‐bisphosphate hydrolysis accompanies T cell receptor‐induced apoptosis of murine thymocytes within the thymus",
abstract = "Regulation of the development of thymocytes into mature T cells within the thymus is now known to involve antigen‐induced deletion, by apoptosis, of potentially autoreactive thymocytes, and it can be mimicked either by stimulating the T cell receptor (TcR) complex by monoclonal antibody (mAb) or by ionophore‐induced elevation of cytosolic [Ca2+]. To identify signaling pathways employed by the TcR complex of immature thymocytes, we examined the effects of anti‐CD3 and anti‐TcR{\ss} constant (c) region mAb, staphylococcal enterotoxin B (SEB) and pharmacological agents on the generation of inositol phosphates through hydrolysis of phosphatidylinositol 4,5‐bisphosphate [PtdIns(4,5)P2] both in cultured fetal mouse thymic lobes and in the CD4+CD8+ immature thymocyte cell line, TM10G. Stimulation of the TcR complex with anti‐CD3 mAb provoked an accumulation of inositol phosphates diagnostic of the occurrence of receptor‐stimulated phosphoinositidase C (PLC) activation. Anti‐TcRC{\ss} mAb and SEB provoked smaller but similar responses. The PLC activation evoked by anti‐CD3 mAb was suppressed by inhibitors of receptor tyrosine kinases and was unmodified by protein kinase C activation or elevation of cytosolic [Ca2+]. It thus appears that apoptosis triggered by TcR stimulation is associated with PLC activation by a receptor‐regulated tyrosine kinase. Treatment of thymic lobes or TM10G cells with fluoroaluminate provoked apoptosis of a wider range of thymocyte subtypes and such stimulation also provoked an accumulation of inositol phosphates. The responses to fluoroaluminate were not prevented by inhibitors of tyrosine kinases, suggesting that unidentified GTP‐binding proteins which couple to PLC activation may also be capable of initiating apoptosis by a route independent of the TcR. These results, when considered alongside previous studies of mature T cells, indicate that stimulation of immature thymocytes or of mature T cells through their TcR complex activates the PLC‐catalyzed PtdIns(4,5)P2 hydrolysis signaling pathway, and thus that this signaling pathway may be implicated both in provoking apoptosis in immature T cells and in initiating proliferation in mature T cells.",
keywords = "Apoptosis, Inositol phosphates, T cell receptor, Thymocytes",
author = "Conroy, {Louise A.} and Jenkinson, {Eric J.} and Owen, {John J.T.} and Michell, {Robert H.}",
year = "1995",
month = jan,
day = "1",
doi = "10.1002/eji.1830250706",
language = "English",
volume = "25",
pages = "1828--1835",
journal = "European Journal of Immunology",
issn = "0014-2980",
publisher = "Wiley-VCH Verlag",
number = "7",

}

RIS

TY - JOUR

T1 - Phosphatidylinositol 4,5‐bisphosphate hydrolysis accompanies T cell receptor‐induced apoptosis of murine thymocytes within the thymus

AU - Conroy, Louise A.

AU - Jenkinson, Eric J.

AU - Owen, John J.T.

AU - Michell, Robert H.

PY - 1995/1/1

Y1 - 1995/1/1

N2 - Regulation of the development of thymocytes into mature T cells within the thymus is now known to involve antigen‐induced deletion, by apoptosis, of potentially autoreactive thymocytes, and it can be mimicked either by stimulating the T cell receptor (TcR) complex by monoclonal antibody (mAb) or by ionophore‐induced elevation of cytosolic [Ca2+]. To identify signaling pathways employed by the TcR complex of immature thymocytes, we examined the effects of anti‐CD3 and anti‐TcRß constant (c) region mAb, staphylococcal enterotoxin B (SEB) and pharmacological agents on the generation of inositol phosphates through hydrolysis of phosphatidylinositol 4,5‐bisphosphate [PtdIns(4,5)P2] both in cultured fetal mouse thymic lobes and in the CD4+CD8+ immature thymocyte cell line, TM10G. Stimulation of the TcR complex with anti‐CD3 mAb provoked an accumulation of inositol phosphates diagnostic of the occurrence of receptor‐stimulated phosphoinositidase C (PLC) activation. Anti‐TcRCß mAb and SEB provoked smaller but similar responses. The PLC activation evoked by anti‐CD3 mAb was suppressed by inhibitors of receptor tyrosine kinases and was unmodified by protein kinase C activation or elevation of cytosolic [Ca2+]. It thus appears that apoptosis triggered by TcR stimulation is associated with PLC activation by a receptor‐regulated tyrosine kinase. Treatment of thymic lobes or TM10G cells with fluoroaluminate provoked apoptosis of a wider range of thymocyte subtypes and such stimulation also provoked an accumulation of inositol phosphates. The responses to fluoroaluminate were not prevented by inhibitors of tyrosine kinases, suggesting that unidentified GTP‐binding proteins which couple to PLC activation may also be capable of initiating apoptosis by a route independent of the TcR. These results, when considered alongside previous studies of mature T cells, indicate that stimulation of immature thymocytes or of mature T cells through their TcR complex activates the PLC‐catalyzed PtdIns(4,5)P2 hydrolysis signaling pathway, and thus that this signaling pathway may be implicated both in provoking apoptosis in immature T cells and in initiating proliferation in mature T cells.

AB - Regulation of the development of thymocytes into mature T cells within the thymus is now known to involve antigen‐induced deletion, by apoptosis, of potentially autoreactive thymocytes, and it can be mimicked either by stimulating the T cell receptor (TcR) complex by monoclonal antibody (mAb) or by ionophore‐induced elevation of cytosolic [Ca2+]. To identify signaling pathways employed by the TcR complex of immature thymocytes, we examined the effects of anti‐CD3 and anti‐TcRß constant (c) region mAb, staphylococcal enterotoxin B (SEB) and pharmacological agents on the generation of inositol phosphates through hydrolysis of phosphatidylinositol 4,5‐bisphosphate [PtdIns(4,5)P2] both in cultured fetal mouse thymic lobes and in the CD4+CD8+ immature thymocyte cell line, TM10G. Stimulation of the TcR complex with anti‐CD3 mAb provoked an accumulation of inositol phosphates diagnostic of the occurrence of receptor‐stimulated phosphoinositidase C (PLC) activation. Anti‐TcRCß mAb and SEB provoked smaller but similar responses. The PLC activation evoked by anti‐CD3 mAb was suppressed by inhibitors of receptor tyrosine kinases and was unmodified by protein kinase C activation or elevation of cytosolic [Ca2+]. It thus appears that apoptosis triggered by TcR stimulation is associated with PLC activation by a receptor‐regulated tyrosine kinase. Treatment of thymic lobes or TM10G cells with fluoroaluminate provoked apoptosis of a wider range of thymocyte subtypes and such stimulation also provoked an accumulation of inositol phosphates. The responses to fluoroaluminate were not prevented by inhibitors of tyrosine kinases, suggesting that unidentified GTP‐binding proteins which couple to PLC activation may also be capable of initiating apoptosis by a route independent of the TcR. These results, when considered alongside previous studies of mature T cells, indicate that stimulation of immature thymocytes or of mature T cells through their TcR complex activates the PLC‐catalyzed PtdIns(4,5)P2 hydrolysis signaling pathway, and thus that this signaling pathway may be implicated both in provoking apoptosis in immature T cells and in initiating proliferation in mature T cells.

KW - Apoptosis

KW - Inositol phosphates

KW - T cell receptor

KW - Thymocytes

UR - http://www.scopus.com/inward/record.url?scp=0029067104&partnerID=8YFLogxK

U2 - 10.1002/eji.1830250706

DO - 10.1002/eji.1830250706

M3 - Article

C2 - 7621860

AN - SCOPUS:0029067104

VL - 25

SP - 1828

EP - 1835

JO - European Journal of Immunology

JF - European Journal of Immunology

SN - 0014-2980

IS - 7

ER -