In this study, we found that the CD8+CD45RA+CCR7− T cell subpopulation was increased in the peripheral blood of patients with primary Sjögren's syndrome (pSS) compared with healthy donors. Moreover, both CD8+TIM-3+ T cells and CD8+CD45RA+CCR7− T cells were positively correlated with serum anti-SSA antibody concentrations in patients. In animal experiments, prolonged administration of β-glucan (whole glucan particle [WGP]) effectively reduced the onset and progression of pSS. Compared with the control group, the WGP-treated group showed a significant reduction in the proportions of CD4+PD-1+ T cells, CD4+TIM-3+ T cells, CD8+PD-1+ T cells, CD8+TIM-3+ T cells, and CD8+CD45RA+CCR7− T cells in the spleens and peripheral blood of non-obese diabetic mice. Notably, β-glucan exhibited therapeutic efficacy comparable to that of hydroxychloroquine sulfate, a conventional treatment for pSS. These findings suggest that the CD8+CD45RA+CCR7− T cell subpopulation may represent a promising new therapeutic target for the disease.