Calcineurin-inhibition drives IL13 and IL5 production in differentiating and memory T cells in a Ca++-dependent manner

The classical Th2 cytokines interleukin 13 (IL13) and 5 (IL5) play an important role in the development of allergies and asthma due to their role in leukocyte recruitment and tissue remodeling. However, IL13 has also been implicated as a major driver of tissue fibrosis. Up to 50% of lung transplant recipients develop fibrotic disease 5-years post-transplantation despite immunosuppressive treatment based on calcineurin inhibitors (CNIs). To investigate the correlation between CNIs and IL13, we isolated naïve and memory T cells from blood of healthy donors and activated with aCD3/aCD28 coated Dynabeads and cytokine cocktails for naïve T cell differentiation in the presence/absence of CNIs for up to 5 days. The readouts investigated were calcium-flux, intracellular and secreted cytokine production and RNA expression by qPCR. Our results show that low-dose CNIs strongly enhances the production of IL13. Strikingly, naïve CD4 T cells that were differentiated in vitro into effector Th1, Th2, Th17 or regulatory T cells in the presence of low dose CNIs increased production of IL5 and IL13 up to 50-fold. Increased IL13 transcription was detected as early as 12hrs after TCR ligation. Pre-treatment of T cells with CNIs increased Ca++-flux upon TCR activation and inhibition of CRAC1 channels on the cell surface blocked the CNI-based IL13-induction, suggesting that this effect was dependent on the influx of extracellular Ca++. Our results suggest that CNI-based immu...
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Mechanisms of Lung Injury and Repair Source Type: research