ABSTRACTCystic echinococcosis (CE) is a common zoonotic parasitic disease that seriously impacts public health. However, the full spectrum of immune cell changes inEchinococcus granulosusinfection, especially the negative immune regulation of subpopulations of regulatory T (Treg) cells, are not yet well understood. In this study, we used single-cell RNA sequencing and immunome repertoire (IR) sequencing to analyze 53,298 cells from the spleens and peripheral blood mononuclear cells (PBMCs) of healthy andE. granulosus-infected mice. We used immunofluorescence combined with RNA fluorescencein situhybridization and quantitative real-time PCR to verify the sequencing results. Our results showed tissue-specific immune system alterations in mice infected withE. granulosus.E. granulosus-infected mice induced a subpopulation of CD4+cells with type I interferon production potential. Furthermore, there were six different Treg cell subpopulationsin vivoat three stages of differentiation, and Treg subpopulations of different classes and different stages of differentiation showed tissue specificity. After infection, the Lag3hiTreg andGpr83+Igfbp4+naive Treg subpopulations were specifically induced in PBMCs and the spleen, respectively. Furthermore, T follicular helper 2 (Tfh2) cells with high expression ofCxxc5andSpock2were found inE. granulosus-infected mice. Our data uncovered changes in the full spectrum of immune cells in mice following the late stages ofE. granulosusinfection, including subpopulations of cells that have not been emphasized in previous studies. These results further enrich the study of the bidirectional immunomodulatory mechanism and offer a different perspective for subsequent studies of infection inE. granulosus.