The recent work of L. Saveanu’s team has been published in Nature Communications

New players in the activation of T Lymphocytes

Cytotoxic T lymphocytes play a major role in the body’s defense against viruses or tumor development. Activation of T cells requires the interaction of their receptor (TCR) with the antigenic peptides presented on the surface of infected cells or tumor cells. These peptides are presented by the molecules of the major class I histocompatibility complex (MHC-I). The interaction between the TCR and the MHC-I / antigenic peptide complex trigger a complex signaling cascade that is responsible for the activation of the T cell. The strength and duration of this signaling cascade can be modulated by several mechanisms, including TCR endocytosis, which until now was considered to terminate the TCR signaling.

A collaborative study between Loredana Saveanu’s team and Sophie Lotersztajn from our center, the Curie Institute and the Necker Institute shows that TCR endocytosis contribute to sustained TCR signaling from endosomal platforms. This endosomal signaling seems particularly important for T cell activation by low affinity antigenic peptides.
To join the endocytic signaling platforms, the CD3ζ chain of TCR is internalized by clathrin-and dynamin- dependent endocytosis. Once internalized, the CD3ζ chain is directed towards intracellular vesicles described by the protein IRAP (Insulin Responsive AminoPeptidase), Syntaxine 6 (Stx6) and Rab4. At this level, after T cell activation, the CD3ζ chain recruits signaling molecules, such as the ZAP-70 kinase. IRAP deletion results in a significant reduction of the intracellular pool of CD3ζ chain and an important decrease of TCR signaling cascade. In addition, mice in which IRAP was specifically deleted in T cells are unable to generate an effective polyclonal anti-tumor T response. This work demonstrates that the TCR is able to signal not only at the plasma membrane, but also from endosomal signaling platforms. This new function of TCR is orchestrated in particular by IRAP and might be relevant for modulation of T cells activation, in particular in T cell based immunotherapies.

Figure legend:
Recruitment of IRAP vesicles, at the immune synapse formed between T cells and mouse dendritic cells (DC). The immune synapse is visualized by the integrin LFA-1.Une étude dirigée par L. Saveanu vient d’être publiée dans Nature Communications