Eukaryotic chaperonin-containing TCP1 drives tubulin dynamics and centrosome structure at immune synaptic contacts.

SUMMARY: CCT is required to regulate interorganelle contact sites through kinesin‐1 dynamics, modulating peroxisome and mitochondria activity, and ultimately controlling lipid cell content and metabolism.

The L-Leu amino acid transporter SLC7A5 has become an important target in inflammation and cancer. However, its role in acute graft-versus-host disease (aGVHD) and graft versus tumor (GVT) remains unexplored. We demonstrate that SLC7A5 deletion affected T cell activation, expansion and survival, and reduced IFNγ and granzyme B expression, thus controlling aGVHD, but without effect on tumor growth. On the other hand, dietary restriction of L-Leu reduced aGVHD by controlling T cell expansion, inducing apoptosis, and affecting granzyme B secretion. However, CD8 T cells did not fail to activate and express IFNγ in the absence of L-Leu, and showed an increased proportion of central memory T cells, which contributed to the GVT response. Deletion of SLC7A5 in T cells compromises mTORC1, glycolysis and mitochondrial oxidation. On the contrary, L-Leu removal reduced mTORC1 and completely blocked glycolysis but preserved mitochondrial function, favoring the generation of central memory responses and expression of stemness marker TCF1. In addition, our metabolomics data underscores the L-Leu-derived metabolite β-hydroxybutyrate as an important marker for SLC7A5-dependent allogenic T cell expansion in aGVHD.

The immune synapse (IS) is a well-known intercellular communication platform, organized at the interphase between the antigen presenting cell (APC) and the T cell. After T cell receptor (TCR) stimulation, signaling from plasma membrane proteins and lipids is amplified by molecules and downstream pathways for full synapse formation and maintenance. This secondary signaling event relies on intracellular reorganization at the IS, involving the cytoskeleton and components of the secretory/recycling machinery, such as the Golgi apparatus and the endolysosomal system (ELS). T cell activation triggers a metabolic reprogramming that involves the synthesis of lipids, which act as signaling mediators, and an increase of mitochondrial activity. Then, this mitochondrial activity results in elevated reactive oxygen species (ROS) production that may lead to cytotoxicity. The regulation of ROS levels requires the concerted action of mitochondria and peroxisomes. In this review, we analyze this reprogramming and the signaling implications of endolysosomal, mitochondrial, peroxisomal, and lipidic systems in T cell activation.