Upregulation of store-operated Ca2+ entry in the naive CD4(+) T cells with aberrant cytokine releasing in active rheumatoid arthritis

作者：Liu Shuang^*; Watanabe Shohei; Shudou Masachika; Kuno Miyuki; Miura Hiromasa; Maeyama Kazutaka

来源：Immunology and Cell Biology, 2014, 92(9): 752-760.

DOI：10.1038/icb.2014.45

The regulated control of Ca2+ influx is essential for the activation and function of the adaptive immune response, as Ca2+ is a key regulator of important transcription factors. To determine whether Ca2+ release-activated Ca2+ (CRAG) channels contribute to the abnormal behaviour of T cells in patients with rheumatoid arthritis (RA), we performed a cross-sectional study to characterize the expression and functional status of CRACM1 channels in RA patients. Peripheral blood was obtained from 50 RA patients, 50 osteoarthritis (OA) patients and healthy donors. We measured Ca2+ influx and CRAG currents in naive and memory CD4(+) T cells. CRACM1 expression was evaluated in T cells from each of the three groups. These cells were further characterized by flow cytometric analysis of interleukin-4 (IL-4), IL-17, interferon-gamma and tumour necrosis factor-alpha. These cytokines were also measured in naive CD4(+) T cells following the lentivirus-mediated silencing of CRACM1. There was a significant positive correlation between Ca2+ influx in naive T cells and RA activity. Functionally aberrant naive CD4(+) T cells from patients with active RA showed the different cytokine release pattern and exhibited increased Ca2+ influx as well as increased CRACM1 protein expression and function. Specific lentiviral-induced gene silencing of CRACM1 reversed the alterations in T-cell cytokine production. The data presented here indicate that an upregulation of CRACM1 expression and function may be responsible for the abnormal cytokine release of naive CD4(+) T cells in RA patients. CRACM1 might therefore represent a new molecular target for RA therapies.

• 出版日期2014-10