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We would like to thank Jose Miguel Rodriguez Frade and Adriana Quijada for their help with apoptosis experiments. We also thank Domingo Barber for MRL/MpJ-Fas^lpr mice, Jesus Salvador for antibodies and Estanislao Nistal-Villan for kindly providing reagents. This work was funded by grants from the Community of Madrid to DB (B2017/BMD-3804) and from Spanish Ministry of Science and Innovation to DB (SAF2016-80803-R) and CMA (SAF2016-75456R and PID2019-110574RB-I00). GR holds Juan de la Cierva Grant (FJCI-2017-32865). None of the funding institutions had the role in the design of the study and collection, analysis and interpretation of the data, and writing of the manuscript.

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Mitochondrial reactive oxygen is critical for IL-12/IL-18-induced IFN-gamma production by CD4(+) T cells and is regulated by Fas/FasL signaling

Publicado en:Cell Death & Disease. 13 (6): 531- - 2022-06-06 13(6), DOI: 10.1038/s41419-022-04907-5

Autores: Rackov, Gorjana; Zaniani, Parinaz Tavakoli; del Pino, Sara Colomo; Shokri, Rahman; Monserrat, Jorge; Alvarez-Mon, Melchor; Martinez-A, Carlos; Balomenos, Dimitrios;

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Mitochondrial activation and the production of mitochondrial reactive oxygen species (mROS) are crucial for CD4(+) T cell responses and have a role in naive cell signaling after TCR activation. However, little is known about mROS role in TCR-independent signaling and in recall responses. Here, we found that mROS are required for IL-12 plus IL-18-driven production of IFN-gamma, an essential cytokine for inflammatory and autoimmune disease development. Compared to TCR stimulation, which induced similar levels of mROS in naive and memory-like cells, IL-12/IL-18 showed faster and augmented mROS production in memory-like cells. mROS inhibition significantly downregulated IFN-gamma and CD44 expression, suggesting a direct mROS effect on memory-like T cell function. The mechanism that promotes IFN-gamma production after IL-12/IL-18 challenge depended on the effect of mROS on optimal activation of downstream signaling pathways, leading to STAT4 and NF-kappa B activation. To relate our findings to IFN-gamma-driven lupus-like disease, we used Fas-deficient memory-like CD4(+) T cells from lpr mice. Importantly, we found significantly increased IFN-gamma and mROS production in lpr compared with parental cells. Treatment of WT cells with FasL significantly reduced mROS production and the activation of signaling events leading to IFN-gamma. Moreover, Fas deficiency was associated with increased mitochondrial levels of cytochrome C and caspase-3 compared with WT memory-like cells. mROS inhibition significantly reduced the population of disease-associated lpr CD44(hi)CD62L(lo)CD4(+) T cells and their IFN-gamma production. Overall, these findings uncovered a previously unidentified role of Fas/FasL interaction in regulating mROS production by memory-like T cells. This apoptosis-independent Fas activity might contribute to the accumulation of CD44(hi)CD62L(lo)CD4(+) T cells that produce increased IFN-gamma levels in lpr mice. Overall, our findings pinpoint mROS as central regulators of TCR-independent signaling, and support mROS pharmacological targeting to control aberrant immune responses in autoimmune-like disease.

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