Altered thymic positive selection and intracellular signals in Cbl-deficient mice
- Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852
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Communicated by William E. Paul, National Institute of Allergy and Infectious Diseases, Bethesda, MD (received for review September 21, 1998)
Abstract
Cbl is the product of the protooncogene c-cbl and is involved in T cell antigen receptor (TCR)-mediated signaling. To understand the role of Cbl for immune system development and function, we generated a Cbl-deficient mouse strain. In Cbl-deficient mice, positive selection of the thymocytes expressing major histocompatibility complex class II-restricted transgenic TCR was significantly enhanced. Two factors may have contributed to the altered thymic selection. First, Cbl deficiency markedly up-regulated the activity of ZAP-70 and mitogen-activated protein kinases. The mitogen-activated protein kinase pathway was shown previously to be involved in thymic positive selection. Second, Cbl-deficient thymocytes expressed CD3 and CD4 molecules at higher levels, which consequently may increase the avidity of TCR/major histocompatibility complex/coreceptor interaction. Thus, Cbl plays a novel role in modulating TCR-mediated multiple signaling pathways and fine-tunes the signaling threshold for thymic selection.
Footnotes
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↵ * M.N. and H.K.K. contributed equally to this work.
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↵ † To whom reprint requests should be addressed at: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12441 Parklawn Drive, Rockville, MD 20852. e-mail: Hgu{at}atlas.niaid.nih.gov.
- ABBREVIATIONS:
- TCR,
- T cell antigen receptor;
- MHC,
- major histocompatibility complex;
- PI-3K,
- phosphatidylinositol-3 kinase;
- PLC,
- phospholipase C;
- MMTV,
- mammary tumor virus;
- wt,
- wild type;
- SP,
- single positive;
- DP,
- double positive
