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The role of endocytic trafficking in antigen T cell receptor activation

This review article summarizes the molecular mechanisms of T cell receptor (TCR) #endocytosis and recycling, both in steady state and after T cell activation. It also discusses the experimental evidence in favor of endosomal TCR signaling and its possible consequences for T cell activation.

Abstract Antigen T cell receptors (TCR) recognize antigenic peptides displayed by the major histocompatibility complex (pMHC) and play a critical role in T cell activation. The levels of TCR complexes at the cell surface, where signaling is initiated, depend on the balance between TCR synthesis, recycling and degradation. Cell surface TCR interaction with pMHC leads to receptor clustering and formation of a tight T cell-APC contact, the immune synapse, from which the activated TCR is internalized. While TCR internalization from the immune synapse has been initially considered to arrest TCR signaling, recent evidence support the hypothesis that the internalized receptor continues to signal from specialized endosomes. Here, we review the molecular mechanisms of TCR endocytosis and recycling, both in steady state and after T cell activation. We then discuss the experimental evidence in favor of endosomal TCR signaling and its possible consequences on T cell activation.

Like all the components of multicellular organisms, T lymphocytes constantly communicate with other cells and their extracellular environment. The plasma membrane plays an essential role in this communication since it expresses a plethora of receptors that are capable of detecting extracellular signals, either by binding soluble mediators, or by recognizing ligands expressed by other cells. The expression of these various receptors at the plasma membrane is precisely controlled by endocytosis, an active process by which small regions of the plasma membrane are internalized and form vesicles that undergo homotypic fusion to generate early endosomes (EE). EE are the main sorting hub for internalized plasma membrane receptors, which can be either recycled back to the plasma membrane, or delivered to lysosomes for degradation (Fig. 1) [1]. The balance between lysosomal degradation and endocytic recycling is essential to preserve a sufficient receptor pool for an optimal ability of cells to adapt to environmental changes. Even if the receptor pool is constantly replenished by newly synthesized molecules, the rate of protein synthesis cannot substitute for the endocytic recycling, which is a rapid and massive process. It is estimated that mammalian cells recycle at least half of their plasma membrane within an hour [2], which probably also applies to T cells. In comparison, protein half-life is much longer varying from 0.5 to 35 h in dividing mammalian cells [3]. Thus, the role of constitutive endocytic recycling on the receptor expression at the cell surface must be major. Beside its important role in regulating the cell surface receptor amounts, accumulating evidence supports the concept that endocytosis also promotes signaling amplification and signal diversification for several receptors that recruit signaling adaptors at the endosomal level [4].

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