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Increased Expression of CD95 in CD4+ Effector Memory T Cells Promotes Th17 Response in Patients with Myasthenia Gravis

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Abstract

Emerging data have revealed that CD95 can evoke non-apoptotic signals, thereby promoting pro-inflammatory functions that link to the severity of autoimmune disorders. Here, we reported that the expression of CD95 in CD4+ effector memory T (CD4+ TEM) cells was increased in myasthenia gravis (MG) patients. We also found increased expression of CD95 in CD4+ TEM cells from MG patients correlated positively with clinical severity scores (QMGs), serum IL-17 levels and plasma cells (PCs) frequencies. Conventional treatment, such as glucocorticoid, could down-regulate the expression of CD95 in CD4+ TEM cells, QMGs, serum IL-17 levels and PCs frequencies from MG patients. In vitro, low-dose of agonistic anti-CD95 mAb could promote Th17 cell development. This effect was reversed by CD95 siRNA. Moverover, CD95 stimulation induced the phosphorylation of p38 and Erk1/2 and Th17 cell differentiation, and p38 specific inhibitor SB203580 or Erk1/2 specific inhibitor PD98059 could induce opposite changes. However, SB203580 or PD98059 do not abrogate the increase of CCR6+IL-17A+ cells, ROR-γt and IL-17 expression induced by CD95 triggering relatively to each corresponding control. This suggests that p38 and Erk1/2 MAPK pathway plays a role in expression of CCR6+IL-17A+ cells, ROR-γt and IL-17, but not in their increase induced by CD95 triggering. Taken together, this study revealed that increased expression of CD95 in CD4+ TEM cells promotes Th17 response under the microenvironment of MG.

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Acknowledgements

This work was supported by The Fifth Phase "333 Project" Scientific Research Subsidy Project in Jiangsu Province (BRA2018395), National Nature Science Foundation of China (81072465, 81571579), Postgraduate Research & Practice Innovation Program of Jiangsu Province (SJCX20_0928), Innovation and entrepreneurship training program for college students in Jiangsu Province (201610313038Y), Key medical talents fund of Jiangsu Province (H201130) and Jiangsu Province ordinary university postgraduate research innovation fund(CXLX11_0734).

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  1. Xiaoyu Huang, Jie Zhu and Tan Liu contributed equally to this work.

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  1. Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China

    Xiaoyu Huang, Jie Zhu, Tan Liu, Fengzhan Li, Tingting Yang, Hao Li, Fei Chen, Yong Zhang, Chenghua Xiao & Deqin Geng

  2. Department of Neurology, Second Affiliated Hospital of Xuzhou Medical University, 32 Coal Construction Road, Quanshan District, Xuzhou, Jiangsu, China

    Jie Zhu & Fei Chen

  3. Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China

    Yuzhong Wang

  4. Department of Pathogenic Biology and Lab of Infection and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China

    Linlin Fu

  5. Department of Neurology, The First People’s Hospital of Huzhou, Huzhou, Zhejiang, China

    Tan Liu

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Huang, X., Zhu, J., Liu, T. et al. Increased Expression of CD95 in CD4+ Effector Memory T Cells Promotes Th17 Response in Patients with Myasthenia Gravis. J Neuroimmune Pharmacol 17, 437–452 (2022). https://doi.org/10.1007/s11481-021-10030-7

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  • DOI: https://doi.org/10.1007/s11481-021-10030-7

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