Researching new targets is essential for treating inflammatory diseases whose number increases steadily in recent decades in industrialized countries. Calpains could be such targets. They are cysteine proteases whose activity is increased by calcium and limited specifically by calpastatin. Calpains are present in T cells whose activation leads to the development of immune and inflammatory diseases. In this study we showed that calpains modulate the intracellular activity of T cells. In addition, these proteins can be externalized. Interestingly intra- and extra-cellular calpains have opposite effects. Indeed, intracellular calpains increase the mobility of T cells and the differentiation of proinflammatory Th17 T cells by limiting IL-2 signalling through the c chain of the IL-2 receptor. In contrast to intracellular calpains, calpains secreted via the ABC transporters A1 (ATP binding cassette A1) act on the protein gp130, a subunit of IL-6 receptor, and thus limit the differentiation of Th17 T cells. A molecule or drug limiting the action of intracellular calpains while promoting their externalization would be a good therapeutic target in the development of inflammatory diseases.
