A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation.

Signaling through the T cell receptor (TCR) controls adaptive immune responses. Antigen binding to TCRαβ transmits signals through the plasma membrane to induce phosphorylation of the CD3 cytoplasmic tails by incompletely understood mechanisms. Here we show that cholesterol bound to the TCRβ transmembrane region keeps the TCR in a resting, inactive conformation that cannot be phosphorylated by active kinases.

CD3ε recruits Numb to promote TCR degradation.

Modulation of TCR signaling upon ligand binding is achieved by changes in the equilibrium between TCR degradation, recycling and synthesis; surprisingly, the molecular mechanism of such an important process is not fully understood. Here, we describe the role of a new player in the mediation of TCR degradation: the endocytic adaptor Numb. Our data show that Numb inhibition leads to abnormal intracellular distribution and defective TCR degradation in mature T lymphocytes.

The endocytic adaptor Numb regulates thymus size by modulating pre-TCR signaling during asymmetric division.

Stem cells must proliferate and differentiate to generate the lineages that shape mature organs; understanding these 2 processes and their interaction is one of the central themes in current biomedicine. An intriguing aspect is asymmetric division, by which 2 daughter cells with different fates are generated. Several cell fate determinants participate in asymmetric division, with the endocytic adaptor Numb as the best-known example.