Dynamin 2-dependent Endocytosis Sustains T-cell Receptor Signaling and Drives Metabolic Reprogramming in T Lymphocytes

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2015 Apr 2

PMID 25831514

Citations 32

Authors

Tim Willinger

Matthew Staron

Shawn M Ferguson

Pietro De Camilli

Richard A Flavell

Affiliations

Soon will be listed here.

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.

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