Regulation And Mechanism Effects Of Th17 On DCs Function In Malaria

Malaria is a type of infectious parasitic disease distributed in the tropics caused by protozoan parasites.In 2020,the World Health Organization(WHO)malaria report indicated that an estimated 229 million new malaria cases are documented worldwide.The African region accounted for 93%of all cases,followed by the Southeast Asia region(3.4%)and eastern Mediterranean region(2%).Malaria kills approximately4 million people worldwide each year,and malaria remains one of the biggest challenges to public health in developing countries.Dendritic cells(DCS),a class of professional antigen-presenting cells(APCs)with the highest capacity for antigen presentation in the body,are key players in the regulation of innate and adaptive immune responses and have multiple immunoregulatory functions.DCs can initiate antigen-specific immune responses,presenting antigens to T cells to elicit immune responses.Helper T cell 17(T helper cell 17)is a newly identified T cell subset that can secrete IL-17 and is important in autoimmune diseases and body defense responses.Early in malaria infection,Th17 cells may be interconnected with related mechanisms for controlling Plasmodium infection,meanwhile Plasmodium infection impairs the function and maturation of DCs,ultimately leading to the attenuation of specific cellular immune responses.The maturation and function of DCs are essential for malaria infection processes and outcomes,and are simultaneously regulated by the differentiation of Th17 cells,which suppress the maturation and function of DCs by regulating their subsets,expression of surface molecules and cytokine secretion patterns.The aim of this study was to investigate the regulatory role of Th17cells on the function and maturation of DCs during the development and progression of malaria by infecting BABL/c mice with lethal Plasmodium yoelii 17XL and exogenously administering Th17 cells with anti-IL-17A m Ab.Female BABL/c mice(6-8 weeks old)were randomly divided into three groups:normal control,Th17 cell depleted(p.y17XL+IL-17 m Ab group),and p.y17XL infected(p.y17XL group).Th17 cell elimination group mice and p.y17XL-infected group mice were intraperitoneally injected with p.y17XL-infected red blood cells(p RBCs)1×10~6/mouse;Mice in the Th17 cell elimination group were intraperitoneally injected with 100 mg anti-IL-17A monoclonal antibody(anti-IL-17mab)1 day after infection,and mice in the normal control group and the p.y17XL infection group were intraperitoneally injected with the same volume of PBS.From3 day post infection,mice in the Th17 elimination group(n=5)and the p.y17XL infection group(n=5)underwent tail vein blood collection for thin blood film preparation,Giemsa staining,and dynamic monitoring of the level of protozoa as well as survival.Spleens were harvested 3 days and 5days after infection,single-cell suspensions were prepared,and the numbers of DCs subsets,surface molecule expression,and IL-10 and IL-12secreting DCs were determined by flow cytometry.At 3 days post infection,Th17 cells accounted for approximately(16.7±3.3)%of CD4~+T cells in the spleen of mice in the p.y17XL infected group,peaked at 5 days post infection,and accounted for approximately(19.6±2.6)%of CD4~+T cells,all significantly higher than those in the normal control group(2.4±0.3)%(P<0.01).At 3 days and 5 days after infection,the Th17 cells were eliminated by 86.2%and 84.1%of the mice in the Th17 elimination group,respectively,which was significantly lower than that in the normal control group,thus demonstrating that the Th17 cell elimination group model was successfully constructed.We also found that the number of DCs subsets and the expression of surface molecules(CD86,MHC-II,and CD80)were significantly increased in the spleens of Th17cell depleted mice at 3 days post infection(P<0.05);However,at 5 days post infection,the number of DCs subsets and the expression of surface molecules(CD80 and MHC-II)in the spleen of Th17 cell depleted mice were significantly reduced(P<0.05);Moreover,the percentages of DCs secreting IL-12 and IL-10 were significantly increased at 5 days post infection in Th17 cell depleted mice,which were 5.8 and 2.5 fold higher,respectively,than those in p.y17XL infected mice on the same day.In the early stage of P.y17XL infection,Th17 cells could effectively suppress the immune function of DCs for a short period of time,followed by rapid recovery of DCs function;the mechanism of action may be closely related to the cytokine secretion pattern,subpopulation number and phenotypic characteristics of Th17-regulated DCs.