Antigens Activation Induced T Help Cells Death Contributed To Th1/Th2 Responses Polarization During Different Stages Of Schistosoma Japonicum Infection

T helper(Th)cells express the CD4~+ antigen and can differentiate into at least two subsets,Th1 and Th2 cells,distinguished by the array of cytokine genes that they express.Th1 cells secrete IL-2,IFN-γand TNF-α,which are important for the eradication of intracellular pathogens,including bacteria,parasites,yeasts and viruses; whereas Th2 cells secrete IL-4,IL-5,IL-6,IL-10,and IL-13 and can activate mast cells and eosinophils,thereby eradicating helminthes and other extracellular parasites. The development of Th1 versus Th2 cells is a major branch point in the immune response.It is an important determinant of whether the response to an infectious pathogen will lead to protection of the host or dissemination of the disease,or even the parasites may use host cell apoptosis as a survival strategy to establish infection in their host by creating a site of immune privilege around them.Schistosoma have provided excellent models for studying the induction and regulation of Th cell subset responses to infection.In the course of an infection,the immune response progresses through at least three phases.In the first 3 weeks, during which the host is exposed to migrating immature parasites,the dominant response is T helper 1(Th1)-like that is induced by non-egg antigens including cercariae,schistosomula and adult worm antigens.As the parasites begin to produce eggs at weeks 3.5-4,the response alters markedly;the Th1 component may decrease and this is associated with the emergence of a strong Th2 response.This response is induced primarily by egg antigens.During the chronic phase of infection,the Th2 response is modulated and granulomas that form around newly deposited eggs are smaller than at earlier times during infection.Many factors influence the differentiation of Th1/Th2 cells,including the dose and form of antigen,the affinity of the peptide antigen - T cell receptor(TCR),the nature and degree of costimulation,APC and the cytokine milieu surrounding the differentiating cells.And now it is established that Th1 and Th2 cells differ also in their tendencies to undergo TCR-induced cell death(TCR-ICD).However,there is very little data available to show the different antigens of a pathogen activation induced Th cells death contributed to Th1/Th2 responses polarization during different stages of infection.In the present study,to determine the antigens activation induced T help cells death contributed to Th1/Th2 responses polarization in different stages of Schistosoma japonicum infection,by using caspase-3 assay we investigated the apoptosis of Th cells from mice at days of 23,35,56 post-infection with or without administration of artesunate.We also investigated the apoptosis of Th cells from the mice immunized with SWA or SEA,and of the CD4~+T cells from normal mice stimulated with SWA or SEA in vitro.Then the lymphocytes from the mice immunized with SWA or SEA were restimulated with SWA or SEA in vitro and in the presence of GrB or caspase inhibitor respectively,and the percentage of the apoptotic Th cells was determined by TUNEL assay to preliminary explore the potential molecular mechanisms.Results showed that in the early-stage of the S.japonicum infection,the immune response induced by non-egg antigens against shistosome parasite was Th1 bias, while the Th2 cells were more susceptible to apoptosis than Th1 cells.After the parasites producing eggs,the host response,mainly induced by egg antigens,shifted toward Th2 bias,meanwhile more Th1 cells went apoptosis than Th2 cells.Further studies showed that SWA activation induced Th2 cells apoptosis was GrB dependent and SEA activation induced Th1 cells apoptosis was caspase dependent.All these suggested that the Th1/Th2 cell apoptosis induced by different schistosome antigens might involved in host Th immune response shift and polarization,and might be used by parasites as a survival strategy to establish infection in their host.