IL-21/IL-21R Promotes Chlamydia Lung Infection Through Regulation Of CD4~+T Cell Response

Background and ObjectiveChlamydia is a strict intracellular bacterium that causes many infectious diseases.Chlamydia pneumoniae and Chlamydia trachomatis are the main strains causing human diseases.Chlamydia trachomatis can cause trachoma,neonatal chlamydia pneumonia and genital tract infections.Specific CD4⁺T cell responses are induced during Chlamydia trachomatis respiratory infection,especially IFN-?secreted by Th1cells provides a key protection.IL-21/IL-21R signal has been reported to regulate the differentiation and function of CD4⁺T cell subsets,exert anti-inflammatory and pro-inflammatory effects.However,the effects of IL-21/IL-21R signaling pathway on the differentiation and function of CD4⁺T cell subsets in Chlamydia respiratory infection was unknown.We intends to explore the effect of IL-21/IL-21R on CD4⁺T cell subsets using IL-21R knockout mice in Chlamydia trachomatis respiratory infections.MethodsIn this study,IL-21R knockout mice were used to investigate the effects of IL-21/IL-21R pathway on the differentiation and function of CD4⁺T cell subsets during Chlamydia respiratory infection.WT mice were intranasally administered with certain amount of Cm,and sacrificed at different time points post-infection.Expression of IL-21 and IL-21R mRNA in lung tissue were detected by RT-PCR to determine whether the IL-21/IL-21R pathway is involved during Chlamydia respiratory infection.Secondly,IL-21R^-/-and WT mice were intranasally inoculated with certain amount of Cm,the role of IL-21/IL-21R pathway plays during Chlamydia respiratory infection was reflected by the change of body weight,pathological change,and IFU.Finally,the changes of IFN-?,IL-4,IL-17 and Foxp3expression in total CD4⁺T cells and CD4⁺T cell subsets in lung were detected by flow cytometry to explore the effect of IL-21/IL-21R pathways on specific CD4⁺T cell response,including Th1,Th2,Th17 and Treg cells,during Chlamydia lung infections.ResultsThe expression of IL-21 mRNA and IL-21R mRNA in lung peaked at day7 and day 14 post-infection respectively,with significant difference compared to uninfected group?p<0.001,p<0.001?.Compared with WT mice,IL-21R^-/-mice had lower body weight loss and better recovery.The weight loss of the two mice was significantly different during day 4 to day11 post-infection?p<0.01?.Compared with WT mice,bacteria load of IL-21R^-/-mice was significantly lower at day 7 post-infection?p<0.01?.Compared with IL-21R^-/-mice,more serious pathological change was observed in lung of WT mice post-infection.The percentage and total number of CD3⁺T cells and CD4⁺T cells in the lung of IL-21R^-/-mice were significantly increased at day7 after infection than WT mice?p<0.05,p<0.001?.Percentage of CD8⁺T cells in lung of IL-21R^-/-mice was significantly lower at day7 post-infection,and the absolute number was significantly lower than WT mice at day14post-infection?p<0.001,p<0.01?.Percentage and the number of CD3⁺IFN-?⁺T cells,Th17 cells and Th1 cells of IL-21R^-/-mice were significantly higher than WT mice at day7 post-infection?p<0.001,p<0.001?.Percentage of Th2 cells in lung of IL-21R^-/-mice was significantly lower than WT mice at day7 post-infection?p<0.05?.At day7post-infection,the percentage of CD4⁺CD25⁺T cells and CD25⁺Foxp3⁺T cells in IL-21R^-/-mice were significantly lower than WT mice?p<0.001,p<0.01?,but the number of CD4⁺CD25⁺T cells and CD25⁺Foxp3⁺T cells in lung tissue of WT mice was significantly higher than IL-21R^-/-mice?p<0.001?.The ratio of Th1/Treg and Th17/Treg in lung tissue of IL-21R^-/-mice were significantly higher than that in WT mice?p<0.001,p<0.01?at day7 post-infection.Conclusion1.IL-21 and IL-21R mRNA expression were induced during Chlamydia respiratory infection,indicating that IL-21/IL-21R signaling pathway was involved in host against Chlamydia infection immune response2.Compared with WT mice,IL-21R knockout mice have less weight loss,less pathological change,and less chlamydial load in lung,indicating that IL-21/IL-21R signaling pathway can promote and aggravate inflammation during Chlamydia lung infection.3.IL-21/IL-21R pathway inhibited the infiltration of CD3⁺T cells in lung tissue in Chlamydia respiratory infection,which mainly inhibited CD4⁺T cells.4.In Chlamydia respiratory infection,IL-21/IL-21R pathway can inhibit the secretion of IFN-?and IL-17 by CD4+T cells,inhibiting specific Th1 and Th17 protective immune response.And pathological response of Th2 cells and immunosuppressive effects of Treg cells were promoted.