Protein arginine methyltransferase 5 promotes cholesterol biosynthesis–mediated Th17 responses and autoimmunity
Lindsay M. Webb, Shouvonik Sengupta, Claudia Edell, Zayda L. Piedra-Quintero, Stephanie A. Amici, Janiret Narvaez Miranda, Makenzie Bevins, Austin Kennemer, Georgios Laliotis, Philip N. Tsichlis, Mireia Guerau-de-Arellano
Lindsay M. Webb, Shouvonik Sengupta, Claudia Edell, Zayda L. Piedra-Quintero, Stephanie A. Amici, Janiret Narvaez Miranda, Makenzie Bevins, Austin Kennemer, Georgios Laliotis, Philip N. Tsichlis, Mireia Guerau-de-Arellano
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Research Article Autoimmunity Immunology

Protein arginine methyltransferase 5 promotes cholesterol biosynthesis–mediated Th17 responses and autoimmunity

Abstract

Protein arginine methyltransferase 5 (PRMT5) catalyzes symmetric dimethylation (SDM) of arginine, a posttranslational modification involved in oncogenesis and embryonic development. However, the role and mechanisms by which PRMT5 modulates Th cell polarization and autoimmune disease have not yet been elucidated. Here, we found that PRMT5 promoted SREBP1 SDM and the induction of cholesterol biosynthetic pathway enzymes that produce retinoid-related orphan receptor (ROR) agonists that activate RORγt. Specific loss of PRMT5 in the CD4+ Th cell compartment suppressed Th17 differentiation and protected mice from developing experimental autoimmune encephalomyelitis (EAE). We also found that PRMT5 controlled thymic and peripheral homeostasis in the CD4+ Th cell life cycle and invariant NK (iNK) T cell development and CD8+ T cell maintenance. This work demonstrates that PRMT5 expression in recently activated T cells is necessary for the cholesterol biosynthesis metabolic gene expression program that generates RORγt agonistic activity and promotes Th17 differentiation and EAE. These results point to Th PRMT5 and its downstream cholesterol biosynthesis pathway as promising therapeutic targets in Th17-mediated diseases.

Authors

Lindsay M. Webb, Shouvonik Sengupta, Claudia Edell, Zayda L. Piedra-Quintero, Stephanie A. Amici, Janiret Narvaez Miranda, Makenzie Bevins, Austin Kennemer, Georgios Laliotis, Philip N. Tsichlis, Mireia Guerau-de-Arellano

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Figure 7

Th cell–specific Prmt5 deficiency prevents induction of EAE autoimmunity.

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Th cell–specific Prmt5 deficiency prevents induction of EAE autoimmunity...
(A) Schematic of tamoxifen treatment/EAE experimental design and downstream analyses. (B) EAE score in iCD4-PRMT5Δ/Δ and indicated controls after MOG35–55/CFA immunization. All mice were treated with tamoxifen by oral gavage before immunization. (C–E) Flow analysis and quantification of CNS-infiltrating (C) CD3+ and CD3+CD4+ T cells or (D and E) naive, Tem, and Tcm phenotype CD4+ T cells from iCD4-PRMT5Δ/Δ and indicated controls 21 days after MOG35–55/CFA immunization. (F–Q) CNS-infiltrating cells (F–K) or splenocytes (L–Q) from day 14 iCD4-PRMT5Δ/Δ and indicated controls were reactivated with MOG35–55. (F and L) Proliferation was monitored by 3H-thymidine incorporation and expressed as a relative proliferation ratio to the resting PRMT5fl/fl media control condition. MOG35–55-reactivated cells were analyzed by ELISA for (G and M) IFN-γ and (H and N) IL-17 secretion, and flow cytometry for (I and O) T-bet+IFN-γ+ Th1, (J and P) RORγt+IL-17+ Th17, and (K and Q) T-bet+IL-17+ cell populations. Data are pooled from 4 independent experiments, n = 6–10 mice. Kruskal-Wallis with Dunn’s multiple-comparisons test (B and Q); 1-way ANOVA followed by Sidak’s multiple-comparisons test (F, L, O, and P) or Student’s t test (C, E, G–K, M, and N). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Box-and-whisker plots boxes extend from 25th to 75th percentiles, all points shown, whiskers extend from min to max, line represents median. Bar graphs are indicated as mean ± SD for F, I–L, O–Q and mean ± SEM for G, H, M, and N. Tem, effector memory T cells; Tcm, central memory T cells; TF, transcription factor; Ck, cytokine.