Inhibition Of T Follicular Helper Cell Immune Response By Myeloid-derived Suppressor Cells In Japanese Encephalitis Virus Infection:A Mechanism Of Immune Evasion

Japanese encephalitis virus(JEV)is a member of the genus flavivirus and belongs to the neurotropic virus.The mosquitoes carry the virus for the media to spread among pigs,birds and humans,causing serious encephalitis of zoonotic infectious disease(Japanese encephalitis,JE).With global warming and frequent contact between humans and carrying pathogenic organisms,insect borne disease intensifies and JE epidemic also shows a rising trend.Although inactivated vaccine and attenuated vaccine have been used for decades for prevention and control of JE,it is still prevalent in Asia and is classified the class II animal disease by the World Animal Health Organization(OIE).Its expanding geographical range and ability to cause devastating epidemics in non-immune populations call for urgent efforts to develop efficient antiviral therapies or alternate strategies to reduce JEV immunopathogenesis.Many studies have focused on the importance of crossing the blood–brain barrier(BBB)in pathogenesis and the immune response of the central nervous system(CNS)during JEV infection.JEV must escape immune surveillance at the periphery until the essential alterations occur at the BBB.Therefore,from the periphery to the CNS,evasion of immune clearance may be a prerequisite for JEV.However,little is known regarding the mechanism by which JEV escapes the immune response at the periphery.In view of the important role of immunosuppression in immune escape mediated by pathogen,this study seeks to identify novel immunosuppressive pathways associated with MDSCs in JEV infected mouse model.Here,we studied Japanese encephalitis virus(JEV)infection leading to immune escape depending on suppression of the adaptive immune responses mediated by the innate cell(Myeloid-derived Suppressor Cells,MDSCs).Firstly,six or eight-week-old age-matched C57BL/6 mice were intravenously injectedwithJEV.MDSCs,TregsandcytokineIL-10 associatedwith immunosuppression was determined by flow cytometry or real-time PCR.The result showed that expanded MDSCs,which was companied by an increase in Tregs and production of IL-10 after JEV infection.However,only MDSCs facilitated the progression of infection,instead of Tregs and IL-10.Secondly,to further study the mechanism of immunosupression mediated by MDSCs,the response of CD4~+T was tested.P3-induced MDSCs suppressed CD4~+T cell immune responses,especially responses of T follicular helper(Tfh)cells,leading to decreased splenic B cells(CD19~+)and blood plasma cells(CD19~+CD138~+).Upon depleting P3-induced MDSCs in vivo,the Tfh cell population,B cells and plasma cells recovered.Lastly,we next questioned whether humoral immune response mediated by Tfh cells was suppressed by P3-induced MDSCs.We compared the level of IgM and viral neutralizing antibodies in the serum in the MDSCs depletion group with the control group,and the results revealed a higher level of IgM and viral neutralizing antibodies production after depletion of MDSCs.In summary,this study identified a new immune evasion pathway by which virus infection-induced MDSCs suppress CD4~+T cells,especially Tfh function and subsequent humoral immune responses in a JEV-infected mouse model.These findings demonstrated an immunosuppressive pathway during JEV infection and highlight the importance of innate cells in inhibiting adaptive immune responses during viral infection.It also provided a new theoretical basis for the treatment of JE and other infectious diseases.