title: Dynamin 2-dependent endocytosis sustains T-cell receptor signaling and drives metabolic reprogramming in T lymphocytes.
abstract: Prolonged T-cell receptor (TCR) signaling is required for the proliferation of T lymphocytes. Ligation of the TCR activates signaling, but also causes internalization of the TCR from the cell surface. How TCR signaling is sustained for many hours despite lower surface expression is unknown. Using genetic inhibition of endocytosis, we show here that TCR internalization promotes continued TCR signaling and T-lymphocyte proliferation. T-cell-specific deletion of dynamin 2, an essential component of endocytosis, resulted in reduced TCR signaling strength, impaired homeostatic proliferation, and the inability to undergo clonal expansion in vivo. Blocking endocytosis resulted in a failure to maintain mammalian target of rapamycin (mTOR) activity and to stably induce the transcription factor myelocytomatosis oncogene (c-Myc), which led to metabolic stress and a defect in cell growth. Our results support the concept that the TCR can continue to signal after it is internalized from the cell surface, thereby enabling sustained signaling and cell proliferation.
authors.affiliation: Departments of Immunobiology and richard.flavell@yale.edu tim.willinger@yale.edu.
authors.forename: Tim
authors.initials: T
authors.lastname: Willinger
authors.affiliation: Departments of Immunobiology and.
authors.forename: Matthew
authors.initials: M
authors.lastname: Staron
authors.affiliation: Cell Biology, Program in Cellular Neuroscience, Neurodegeneration and Repair, and.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Ferguson
authors.affiliation: Cell Biology, Program in Cellular Neuroscience, Neurodegeneration and Repair, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
authors.affiliation: Departments of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520 richard.flavell@yale.edu tim.willinger@yale.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001343:Autophagy; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D034285:Dynamin II / Q000502:physiology*; D004705:Endocytosis; D005786:Gene Expression Regulation; D007167:Immunotherapy; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D016271:Proto-Oncogene Proteins c-myc; D011948:Receptors, Antigen, T-Cell; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D034285:Dynamin II
keywords: T-cell receptor; endocytosis; metabolism; proliferation
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