DOI: 10.4049/jimmunol.163.2.715. Activation of the Extracellular Signal-Related Kinase/Mitogen-Activated Protein Kinase Pathway Discriminates CD4 Versus CD8 Lineage Commitment in the Thymus

Activation of the Extracellular Signal-Related Kinase/Mitogen-Activated Protein Kinase Pathway Discriminates CD4 Versus CD8 Lineage Commitment in the Thymus

10.4049/jimmunol.163.2.715

Crossref journal-article

Oxford University Press (OUP)

The Journal of Immunology (286)

Abstract

AbstractWe have investigated the role of the mitogen-activated protein kinase (MAPK) pathway in the differentiation of CD4+ and CD8+ T cells by looking specifically at the effects of inhibitors of MAPK-activating enzyme, MAPK/extracellular signal-related kinase (ERK) kinase (MEK), during the positive selection step from double-positive to single-positive (SP) thymocytes. Using a variety of transgenic/knockout mouse strain combinations that fail to differentiate individual lineages of SP thymocytes together with genetically engineered F(ab′)2 reagents that induce maturation preferentially to either the CD4 or CD8 subpopulations, we show that induction of CD4 differentiation cells is highly sensitive to levels of MEK inhibition that have no effect on CD8 maturation. In addition, the presence of MEK inhibitor is able to modify signals that normally induce CD4 differentiation to instead promote CD8 differentiation. Finally, we show that continuous culture in the presence of inhibitor interferes with TCR up-regulation in SP thymocytes, suggesting that MAPK signaling may be involved in final maturation steps for both lineages. These data indicate that there is discrimination in the biochemical pathways that are necessary to specify CD4 and CD8 lineage commitment and can reconcile previously conflicting reports on the influence of MAPK activation in commitment and maturation of thymocytes.

Bibliography

Bommhardt, U., Basson, M. A., Krummrei, U., & Zamoyska, R. (1999). Activation of the Extracellular Signal-Related Kinase/Mitogen-Activated Protein Kinase Pathway Discriminates CD4 Versus CD8 Lineage Commitment in the Thymus. The Journal of Immunology, 163(2), 715â722.

Authors 4

Ursula Bommhardt (first)
M. Albert Basson (additional)
Ulrike Krummrei (additional)
Rose Zamoyska (additional)

References 37 Referenced 68

Dates

Type	When
Created	2 years, 8 months ago (Dec. 31, 2022, 10:11 a.m.)
Deposited	8 months ago (Jan. 2, 2025, 11:30 a.m.)
Indexed	1 week, 3 days ago (Aug. 23, 2025, 9:21 p.m.)
Issued	26 years, 1 month ago (July 15, 1999)
Published	26 years, 1 month ago (July 15, 1999)
Published Print	26 years, 1 month ago (July 15, 1999)

Funders 0

None

BibTeX

@article{Bommhardt_1999, title={Activation of the Extracellular Signal-Related Kinase/Mitogen-Activated Protein Kinase Pathway Discriminates CD4 Versus CD8 Lineage Commitment in the Thymus}, volume={163}, ISSN={1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.163.2.715}, DOI={10.4049/jimmunol.163.2.715}, number={2}, journal={The Journal of Immunology}, publisher={Oxford University Press (OUP)}, author={Bommhardt, Ursula and Basson, M. Albert and Krummrei, Ulrike and Zamoyska, Rose}, year={1999}, month=jul, pages={715–722} }

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      "DOI": "10.1016/0092-8674(94)90169-4"
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      "DOI": "10.1016/0092-8674(94)90505-3"
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      "DOI": "10.1084/jem.187.8.1249"
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    },
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    },
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      "key": "2022123114542635700_R17",
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      "DOI": "10.1084/jem.176.6.1693"
    },
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      "doi-asserted-by": "crossref",
      "unstructured": "Swan, K. A., I. J. Alberola, J. A. Gross, M. W. Appleby, K. A. Forbush, J. F. Thomas, R. M. Perlmutter. 1995. Involvement of p21ras distinguishes positive and negative selection in thymocytes. EMBO J.\u200814: 276",
      "DOI": "10.1002/j.1460-2075.1995.tb07001.x"
    },
    {
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      "unstructured": "Alberola-Ila, J., K. A. Forbush, R. Seger, E. G. Krebs, R. M. Perlmutter. 1995. Selective requirement for MAP kinase activation in thymocyte differentiation. Nature\u2008373: 620",
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    },
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      "doi-asserted-by": "crossref",
      "unstructured": "Sharp, L. L., D. A. Schwarz, C. M. Bott, C. J. Marshall, S. M. Hedrick. 1997. The influence of the MAPK pathway on T cell lineage commitment. Immunity\u20087: 609",
      "DOI": "10.1016/S1074-7613(00)80382-9"
    },
    {
      "key": "2022123114542635700_R28",
      "doi-asserted-by": "crossref",
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      "DOI": "10.1016/S1074-7613(00)80639-1"
    },
    {
      "key": "2022123114542635700_R29",
      "doi-asserted-by": "crossref",
      "unstructured": "Crompton, T., K. C. Gilmour, M. J. Owen. 1996. The MAP kinase pathway controls differentiation from double-negative to double-positive thymocyte. Cell\u200886: 243",
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      "key": "2022123114542635700_R30",
      "doi-asserted-by": "crossref",
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      "DOI": "10.1002/eji.1830260531"
    },
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      "key": "2022123114542635700_R31",
      "doi-asserted-by": "crossref",
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      "DOI": "10.1084/jem.185.8.1413"
    },
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