Abstract
T cell activation is immediately followed by internalization of the T cell receptor (TCR). TCR endocytosis is required for T cell activation, but the mechanisms supporting removal of TCR from the cell surface remain incompletely understood. Here we report that TCR endocytosis is linked to the clathrin-independent carrier (CLIC) and GPI-enriched endocytic compartments (GEEC) endocytic pathway. We show that unlike the canonical clathrin cargo transferrin or the adaptor protein Lat, internalized TCR accumulates in tubules shaped by the small GTPase Cdc42 and the Bin/amphiphysin/Rvs (BAR) domain containing protein GRAF1 in T cells. Preventing GRAF1-positive tubules to mature into endocytic vesicles by expressing a constitutively active Cdc42 impairs the endocytosis of TCR, while having no consequence on the uptake of transferrin. Together, our data reveal a link between TCR internalization and the CLIC/GEEC endocytic route supported by Cdc42 and GRAF1.
Highlights
T cell activation rapidly leads to internalization of T cell receptor (TCR) [1]
Our data reveal a link between TCR internalization and the clathrin-independent carrier (CLIC)/GPI-enriched endocytic compartments (GEEC) endocytic route supported by Cdc42 and GRAF1
Previous work indicates that GRAF1 is a marker of tubular invaginations leading to CLIC-mediated internalization of cargoes [24,26,27]
Summary
T cell activation rapidly leads to internalization of T cell receptor (TCR) [1]. Removal of TCR from the cell surface serves to down-modulate its signalling in order to prevent overactivation [2,3] and is correlated with the stimulation outcome during selection in the thymus [4,5]. Like TCR endocytosis, the Cdc42-mediated CLIC/GEEC pathway relies on cholesterol within the plasma membrane [18]. Cdc42-mediated CLIC/GEEC pathway in activated T cells. The CLIC/GEEC endocytic pathway relying on Cdc is tightly related to GRAF1, a Bin/amphiphysin/Rvs (BAR) domain-containing protein, which senses and promotes membrane curvature [24]. Our data further revealed that GRAF1-positive tubules resulting from Cdc42-Q61L expression contained TCRζ and were still connected to the plasma membrane, suggesting that TCR is internalized through an endocytic pathway involving Cdc42/GRAF1. The GRAF1-positive tubules did not contain the canonical CME cargo transferrin (Tf) In accordance with these results, expression of Cdc42-Q61L impairs internalization of the TCR-CD3 complex but not of Tf, further indicating that endocytosis of TCR could be mediated by a CLIC pathway relying on Cdc and GRAF1
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