Systemic lupus erythematosus (SLE) is a severe autoimmune disease characterized by autoantibody production and multi-organ involvement. Anifrolumab, a monoclonal antibody targeting the type I interferon (IFN) receptor, has been approved for the treatment of SLE. Our aim was to investigate the long-term effects of inhibited type I IFN signaling on circulating follicular helper T subsets (T), follicular regulatory T cells (T), and B lymphocyte subpopulations, reflecting the ongoing germinal center reactions in SLE patients. Peripheral blood samples were obtained from ten SLE patients before the initiation of anifrolumab treatment, and at months 6 and 12 of the intervention period. Flow cytometry analysis was performed to assess the frequencies of circulating T cell subsets, T cells, and certain B cell subpopulations. Serological parameters, including autoantibody levels and complement components, were determined as part of the routine diagnostic evaluation. We observed a significant and sustained reduction in the percentage of activated circulating T cells. Notably, the frequency of CXCR3CCR6 T17 cells decreased, whereas the proportion of CXCR3CCR6 T1 cells increased significantly. Furthermore, the proportion of the IgDCD27 double-negative B lymphocytes was also significantly reduced. These findings suggest that anifrolumab therapy attenuates T cell activation, which may contribute to its clinical efficacy by modulating germinal center responses in SLE.