Myeloid-derived Suppressor Cells Regulate Immunological Memory Formation During Japanese Encephalitis Virus Infection

Japanese encephalitis(JE)is an infectious disease of the central nervous system caused by Japanese encephalitis virus(JEV),a zoonotic mosquito-borne flavivirus.JEV is prevalent in much of Asia and the Western Pacific,with over 4 billion people living at risk of infection.In the absence of antiviral intervention,vaccination is the only strategy to develop long-term sustainable protection against JEV infection.The formation of immunological memory is the basis of the protective immunity induced by vaccine.Thus,it is necessary to explore the factors that affect the formation of immunological memory against JEV,to better understand the immune response during JEV infection,and to help the design of new vaccine against JEV.In this study,the 6~8 week old female C57BL/6 mice were infected with 103 PFU of JEV intravenously(i.v.).After injection,cells were isolated from mouse spleen,lymph nodes,bone marrow,and then analyzed by flow cytometry for the immunological memory-related molecules and cells.To study the effect of myeloid-derived suppressor cells(MDSCs)on immune memory,depletion and transplantation mouse models of MDSCs were established,and re-challenge with the same JEV virus was performed on mice.The results showed that the percentage of CD8+ MPECs,CD127,CD4TCM/TEM,CD8TCM/TEM cells in JEV-P3 group was higher than the SA14-14-2 group;the percentage of GC B,Tfh,LL-PCs,CD8+ SLECs cells in the SA14-14-2 group was higher than the P3 group;depletion and adoptive transfer of MDSCs proved that MDSCs were sufficient for mediating immune suppression of CD8+ MPECs,CCR7,CD4TCM/TEM,CD8TCM/TEM,GC B,Tfh,Bmem,LL-PCs cells in vivo during primary infection;depletion of MDSCs in vivo halted suppression of T cell activation and germinal center responses during secondary infection.Thus,we conclude that SA14-14-2 preferentially forms T-cell immunological memory;P3 preferentially forms B-cell immunological memory;P3-induced MDSCs were sufficient in mediating immune suppression via inhibiting the formation of immunological memory and further impaired the magnitude of secondary responses.This study evaluates the difference of immunological memory formation of SA14-14-2 and P3,and demonstrates an important role for MDSCs in regulating memory differentiation,and these findings could help design new vaccines against JE.