Sphingosine Kinase 2 mediates LCMV-induced CD4(+) T cell suppression and instigates viral persistence while preventing immunopathology
- Authors
- Studstill, Caleb J.; Pritzl, Curtis J.; Seo, Young-Jin; Kim, Dae Y.; Xia, Chuan Z.; Wolf, Jennifer J.; Vijayan, Madhuvanthi; Hahm, Bumsuk
- Issue Date
- May-2019
- Publisher
- American Association of Immunologists
- Citation
- Journal of Immunology, v.202, no.sup.1
- Journal Title
- Journal of Immunology
- Volume
- 202
- Number
- sup.1
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/54186
- DOI
- 10.4049/jimmunol.202.Supp.197.5
- ISSN
- 0022-1767
1550-6606
- Abstract
- Viruses often establish persistent infections by causing dysfunctional T cell responses. Little is known about the role of sphingosine kinase 2 (SphK2) in the immune response to viral infections; even though, its enzymatic product, sphingosine 1-phosphate, is well-known to regulate versatile cellular processes. In this work, we demonstrate that during lymphocytic choriomeningitis virus clone 13 (LCMV Cl 13) infection in mice, SphK2 functions to limit CD4+ T cell responses, which aids in the establishment of virus-induced immunosuppression and viral persistence. The infection of SphK2-deficient (SphK2−/−) mice with LCMV Cl 13 resulted in kidney disease and ultimately mortality, which was not observed with acute infection by the Armstrong strain of LCMV. Following infection, SphK2−/− mice were shown to have increased LCMV-specific CD4+ and CD8+ T cell responses. Depletion of CD4+ or CD8+ T cells prevented the infection-induced death of SphK2−/− mice, which indicates T cell-mediated immunopathology. With the use of LCMV epitope-specific TCR transgenic mouse lines for adoptive transfer studies, SphK2 was shown to have intrinsic negative function in CD4+ T cells, but not CD8+ T cells. Furthermore, SphK2−/− CD4+ T cells were able to promote endogenous, virus-specific CD8+ T cell responses. Importantly, oral treatment of LCMV Cl 13-infected mice with an SphK2-selective inhibitor increased the number of LCMV-reactive CD4+ and CD8+ T cells, and led to the accelerated termination of LCMV Cl 13 persistence, without causing mortality. Our results suggest that transient SphK2 inhibition is a promising novel immunotherapeutic strategy for the control of persistent viral infections.
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Collections - College of Natural Sciences > Department of Life Science > 1. Journal Articles
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