Ansari Abdul Wahid, Ahmad Fareed, Raheed Thesni, Jochebeth Anh, Mateo Jericha Miles Pamiloza, Abdulrahman Nabeel, Joy Elizabeth Febu, Alam Majid Ali, Buddenkotte Joerg, Hamoudi Rifat Akram, Steinhoff Martin
Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
Int Immunopharmacol. 2023 Nov;124(Pt A):110831. doi: 10.1016/j.intimp.2023.110831. Epub 2023 Aug 24.
The precise mechanism of macrolide antibiotic azithromycin (AZM) mediated CD4+ T cell suppression is not fully understood. Given the crucial role of co-stimulatory signaling in T-lymphocyte function, we tested in vitro effects of AZM on two of the most extensively investigated costimulatory molecules, ICOS and OX40 in context to CD4+ T cell proliferation. Using multi-color flow cytometry approach on TCR-activated healthy donor peripheral blood mononuclear cells, we observed a marked reduction in the frequencies and surface expression of ICOS and OX40 receptors following AZM treatment. Functionally, in contrast to ICOS- and OX40- CD3+ CD4+ T cells, AZM treated ICOS+ and OX40+ displayed profound reduction in cell proliferation. Furthermore, AZM treated T cells displaying reduced levels of ICOS and OX40 found to be associated with suppressed mTOR activity as detected by phosphorylation levels of S6 ribosomal protein. This study provides new insights on potential mechanism of AZM mediated inhibition of T cell proliferation by targeting costimulatory pathways.
大环内酯类抗生素阿奇霉素（AZM）介导的CD4+ T细胞抑制的确切机制尚未完全明确。鉴于共刺激信号在T淋巴细胞功能中的关键作用，我们在体外测试了AZM对两种研究最为广泛的共刺激分子ICOS和OX40的影响，以及它们与CD4+ T细胞增殖的关系。通过对TCR激活的健康供体外周血单个核细胞采用多色流式细胞术方法，我们观察到AZM处理后ICOS和OX40受体的频率和表面表达显著降低。在功能上，与ICOS-和OX40- CD3+ CD4+ T细胞相比，经AZM处理的ICOS+和OX40+细胞的增殖显著降低。此外，经AZM处理的T细胞中ICOS和OX40水平降低，通过S6核糖体蛋白的磷酸化水平检测发现其与mTOR活性受到抑制有关。本研究通过靶向共刺激途径，为AZM介导的T细胞增殖抑制的潜在机制提供了新的见解。
