T cell leukemia-1 modulates TCR signal strength and IFN-gamma levels through phosphatidylinositol 3-kinase and protein kinase C pathway activation.
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.
Hoyer
Katrina K
KK
Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California-Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
Herling
Marco
M
Bagrintseva
Ksenia
K
Dawson
David W
DW
French
Samuel W
SW
Renard
Mathilde
M
Weinger
Jason G
JG
Jones
Dan
D
Teitell
Michael A
MA
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism*; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000276:immunology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology
D000954:Antigens, Surface; D017252:CD3 Complex; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; C090851:TCL1A protein, human; C490393:Tcl1 protein, mouse; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C