Sphingosine kinase 2 restricts T cell immunopathology but permits viral persistence
Caleb J. Studstill, … , Sang-Myeong Lee, Bumsuk Hahm
Caleb J. Studstill, … , Sang-Myeong Lee, Bumsuk Hahm
Published September 8, 2020
Citation Information: J Clin Invest. 2020;130(12):6523-6538. https://doi.org/10.1172/JCI125297.
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Research Article Immunology Virology

Sphingosine kinase 2 restricts T cell immunopathology but permits viral persistence

Abstract

Chronic viral infections are often established by the exploitation of immune-regulatory mechanisms that result in nonfunctional T cell responses. Viruses that establish persistent infections remain a serious threat to human health. Sphingosine kinase 2 (SphK2) generates sphingosine 1-phosphate, which is a molecule known to regulate multiple cellular processes. However, little is known about SphK2’s role during the host immune responses to viral infection. Here, we demonstrate that SphK2 functions during lymphocytic choriomeningitis virus Cl 13 (LCMV Cl 13) infection to limit T cell immune pathology, which subsequently aids in the establishment of virus-induced immunosuppression and the resultant viral persistence. The infection of Sphk2-deficient (Sphk2–/–) mice with LCMV Cl 13 led to the development of nephropathy and mortality via T cell–mediated immunopathology. Following LCMV infection, Sphk2–/– CD4+ T cells displayed increased activity and proliferation, and these cells promoted overactive LCMV Cl 13–specific CD8+ T cell responses. Notably, oral instillation of an SphK2-selective inhibitor promoted protective T cell responses and accelerated the termination of LCMV Cl 13 persistence in mice. Thus, SphK2 is indicated as an immunotherapeutic target for the control of persistent viral infections.

Authors

Caleb J. Studstill, Curtis J. Pritzl, Young-Jin Seo, Dae Young Kim, Chuan Xia, Jennifer J. Wolf, Ravi Nistala, Madhuvanthi Vijayan, Yong-Bin Cho, Kyung Won Kang, Sang-Myeong Lee, Bumsuk Hahm

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Figure 6

RNA-Seq analysis reveals changes in cellular transcription and cell cycle processes for SphK2-deficient virus-specific CD4+ T cells.

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RNA-Seq analysis reveals changes in cellular transcription and cell cycl...
(A–E) SphK2-sufficient or -deficient CD45.1+ GP61/CD4+ T cells were adoptively transferred into WT mice, which were then infected with LCMV Cl 13 (n = 3 mice/group). At 7 dpi, CD4+ T cells were column purified from the spleen and inguinal lymph node of mice and sorted for CD45.1+ expression by FACS. RNA was extracted from CD45.1+ cells and assessed for RNA-Seq. (A and B) DE analysis of genes with FDR of less than 0.05. (C) The log2 fold change for the top 12 genes that are upregulated or downregulated in the SphK2-deficient phenotype are shown. (D) Pathway analysis of GO gene sets with a significance FDR of less than 0.1 that correlates with the SphK2-deficient phenotype (red) or SphK2-sufficient phenotype (blue). Gene sets are grouped into clusters based on similar terminology, and lines connect gene sets that have equal to or greater than 75% identical genes. (E) Normalized enrichment scores (NES) for representative gene sets from the GO and Hall molecular signature databases that are correlated with the SphK2-deficient phenotype (positive values) or SphK2-sufficient phenotype (negative values) following GSEA.