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 4

The expression of SphK2 in CD4+ T cells, but not in CD8+ T cells, is required for the inhibition of T cell expansion upon infection.

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The expression of SphK2 in CD4+ T cells, but not in CD8+ T cells, is req...
(A and B) SphK2-sufficient or -deficient Thy1.1+ GP33/CD8+ T cells were adoptively transferred to WT mice which were subsequently infected with LCMV Cl 13 (n = 4 mice/group). (B) At 8 dpi, the accumulation of Thy1.1+ CD8+ cells in the spleen was determined. (C–E) (C) 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 = 3–4 mice/group). At 8 dpi, the expansion of transferred CD45.1+CD4+ cells (D and E) was assessed in the spleen. (F) Sphk2+/+ (upper panel; open histogram) or Sphk2–/– (lower panel; filled histogram) GP61-specific CD4+ T cells labeled with CFSE were incubated with LCMV Cl 13–infected BM-DCs. 5 days after coculture, the CFSE dilution level was measured by flow cytometry analysis. Dotted lines represent CFSE-stained T cells measured at day 0. (G and H) Western blot analysis of SphK2 phosphorylation in splenocytes (G) and purified CD4+ T cells (H) from uninfected, LCMV Arm-infected, or LCMV Cl 13–infected mice (n = 3–4 mice/group) at 8 dpi. Densitometric analysis is represented as the relative expression to the uninfected group, and GAPDH served as an internal control in each group. *P ≤ 0.05; **P ≤ 0.01, 1-way ANOVA with Tukey’s post hoc test (B and E) or Dunnett’s test (G and H). Data are representative of 2–3 independent experiments.