La singularité de la signalisation calcique dans les lymphocytes : possibles implications thérapeutiques dans l'allergie

Effector T lymphocytes include Th1, Th2, Th17 lymphocytes producing different sets of cytokines and exert specialized functions. Th2-cells produce interleukin (IL)-4, 5 and 13 contributing to the elimination of parasites, but they can cause allergic asthma. Except immunotherapy, treatments for asthma are symptomatic and novel strategies are needed. Intracellular calcium concentration ([Ca]i) is tightly regulated in lymphocytes and [Ca]i variations control almost lymphocyte functions. However, this regulation differs depending upon the lymphocyte subset, suggesting the possibility to selectively target a population of lymphocytes responsible for a given disease. Calcium channels at the cell membrane are responsible for calcium entry from the external medium in the cell. ORAI channels are classically described in T-lymphocytes but other calcium channels as Cav1 channels contribute to calcium signaling in T-lymphocytes. Four genes (from Cav1.1 to Cav1.4) encode Cav1 channels. We showed that Cav1.2 and at a lesser degree Cav1.3 channels are selectively expressed by murine Th2 cells and the inhibition of each or the other isoform strongly reduced the calcium response and their cytokine production. In addition, a mix of antisense oligonucleotides specific for Cav1.2 and Cav1.3 protects mice against experimental asthma. We also showed that Cav1.2 was selectively expressed in human Th2 isolated from blood donors. We now aim to determine the level of Cav1 expression in lymphocytes of asthmatic patients and to assess if these channels are expressed in lung inflammatory cell. Another objective concerns the identification of key-molecules selectively implicated in Th2 calcium signaling, which could pinpoint novel targets in the treatment of allergic diseases.