Cell volume controlled by LRRC8A-formed volume-regulated anion channels fine-tunes T cell activation and function.

Biosynthesis drives the cell volume increase during T cell activation. However, the contribution of cell volume regulation in TCR signaling during T lymphoblast formation and its underlying mechanisms remain unclear. Here we show that cell volume regulation is required for optimal T cell activation. Inhibition of VRACs (volume-regulated anion channels) and deletion of leucine-rich repeat-containing protein 8A (LRRC8A) channel components impair T cell activation and function, particularly under weak TCR stimulation. Additionally, LRRC8A has distinct influences on mRNA transcriptional profiles, indicating the prominent effects of cell volume regulation for T cell functions. Moreover, cell volume regulation via LRRC8A controls T cell-mediated antiviral immunity and shapes the TCR repertoire in the thymus. Mechanistically, LRRC8A governs stringent cell volume increase via regulated volume decrease (RVD) during T cell blast formation to keep the TCR signaling molecules at an adequate density. Together, our results show a further layer of T cell activation regulation that LRRC8A functions as a cell volume controlling "valve" to facilitate T cell activation.

CAR-T Cell Therapy in Cancer: Tribulations and Road Ahead.

Chimeric antigen receptor- (CAR-) T cell therapy is one of the most recent innovative immunotherapies and is rapidly evolving. Like other technologies, CAR-T cell therapy has undergone a long development process, and persistent explorations of the actions of the intracellular signaling domain and make several improvements have led to the superior efficacy when anti-CD19 CAR-T cell treatments in B cell cancers. At present, CAR-T cell therapy is developing rapidly, and many clinical trials have been established on a global scale, which has great commercial potential. This review mainly describes the toxicity of CAR-T cell therapy and the challenges of CAR-T cells in the treatment of solid tumors, and looks forward to future development and opportunities for immunotherapy and reviews major breakthroughs in CAR-T cell therapy.