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 7

SphK2 inhibition enhances virus-specific T cell responses.

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SphK2 inhibition enhances virus-specific T cell responses. (A–C) LCMV Cl...
(A–C) LCMV Cl 13–infected mice (n = 5–6 mice/group) were treated with 100 mg/kg ABC294640 (iSphK2) or its solvent by oral gavage each day from day 0 to 2 dpi. At 5 dpi, the numbers of GP33 Tet+CD8+ T cells (B) or GP66 Tet+CD4+ T cells (C) in the spleen were assessed by flow cytometry. (D–F) LCMV Cl 13–infected mice (n = 4–6 mice/group) were treated for 7 days with 100 mg/kg iSphK2 from day 0 to 6 dpi. At 42 dpi, the number of IFN-γ–producing NP396/CD8+ (E) and GP66 Tet+CD4+ (F) T cells were determined in the spleen. (G–L) LCMV Cl 13–infected mice (n = 3–5 mice/group) were treated with solvent (0 mg/kg), 50 mg/kg, or 100 mg/kg iSphK2. At 40 dpi, spleen (G–I) and liver (J–L) tissues were analyzed by flow cytometry for the percentage of IFN-γ+TNF-α+GP33 Tet+CD8+ T cells (G and J), and the MFI of LAG-3 (H and K), PD-1 (I), and Tim-3 (L) on GP33 Tet+ CD8+ T cells. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001, bidirectional, unpaired Student’s t test (B, C, E, and F), 1-way ANOVA with Tukey’s post hoc test (G–L). Data are representative of 2–3 independent experiments.