Sphingosine Kinase 2 mediates LCMV-induced CD4+ T cell suppression and instigates viral persistence while preventing immunopathology

• Published in: The Journal of immunology (1950) 2019-05, Vol.202 (1_Supplement), p.197-197.5
• Main Authors: Studstill, Caleb J, Pritzl, Curtis J., Seo, Young-Jin, Kim, Dae Y., Xia, Chuan Z., Wolf, Jennifer J, Vijayan, Madhuvanthi, Hahm, Bumsuk
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.202.Supp.197.5

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.