Abstract
A signaling role for T cell leukemia-1 (TCL1) during T cell development or in premalignant T cell expansions and mature T cell tumors is unknown. In this study, TCL1 is shown to regulate the growth and survival of peripheral T cells but not precursor thymocytes. Proliferation is increased by TCL1-induced lowering of the TCR threshold for CD4(+) and CD8(+) T cell activation through both PI3K-Akt and protein kinase C-MAPK-ERK signaling pathways. This effect is submaximal as CD28 costimulation coupled to TCL1 expression additively accelerates dose-dependent T cell growth. In addition to its role in T cell proliferation, TCL1 also increases IFN-gamma levels from Th1-differentiated T cells, an effect that may provide a survival advantage during premalignant T cell expansions and in clonal T cell tumors. Combined, these data indicate a role for TCL1 control of growth and effector T cell functions, paralleling features provided by TCR-CD28 costimulation. These results also provide a more detailed mechanism for TCL1-augmented signaling and help explain the delayed occurrence of mature T cell expansions and leukemias despite tumorigenic TCL1 dysregulation that begins in early thymocytes.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, Surface / metabolism
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CD3 Complex / metabolism
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / enzymology
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CD4-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / enzymology
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CD8-Positive T-Lymphocytes / immunology
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Cell Differentiation / immunology
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Cell Line, Tumor
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Cell Proliferation
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Cell Survival / immunology
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Cells, Cultured
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Enzyme Activation / immunology
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Humans
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Interferon-gamma / biosynthesis
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Interferon-gamma / metabolism*
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Jurkat Cells
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Leukemia, T-Cell / enzymology
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Leukemia, T-Cell / immunology
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Leukemia, T-Cell / pathology
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MAP Kinase Signaling System / immunology*
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Mice
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphatidylinositol 3-Kinases / physiology*
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Protein Kinase C / metabolism
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Protein Kinase C / physiology*
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / physiology*
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Receptors, Antigen, T-Cell / metabolism
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Receptors, Antigen, T-Cell / physiology*
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Stem Cells / cytology
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Stem Cells / enzymology
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Stem Cells / immunology
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T-Lymphocytes / cytology
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T-Lymphocytes / enzymology
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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Th1 Cells / cytology
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Th1 Cells / enzymology
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Th1 Cells / immunology
Substances
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Antigens, Surface
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CD3 Complex
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Proto-Oncogene Proteins
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Receptors, Antigen, T-Cell
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TCL1A protein, human
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Tcl1 protein, mouse
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Interferon-gamma
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Phosphatidylinositol 3-Kinases
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Protein Kinase C