Members of the vanin gene family include VNN1 , VNN2 , and VNN3 in humans. Although the functions of vanins have been widely examined in myeloid cells, their expression and functions have not been clarified in T lymphocytes. This study aimed to elucidate the significance of Vanin-2 (VNN2) on human peripheral blood T lymphocytes and study its expression in systemic lupus erythematosus (SLE). The differential expression of Vanins was analyzed by bioinformatics. VNN2 expressions in peripheral blood T-cell subsets were analyzed by single-cell RNA sequencing data and flow cytometry. Changes of VNN2 expression before and after T-cell activation were further clarified by western blot. The function of VNN2 cells was studied by granzyme B (GZMB) and perforin detection. Changes in VNN2 proportions in T-cell subsets of patients with SLE were further analyzed. In the present study, only VNN2 among vanins showed distinguishable expression in T cells. VNN2 percentages were higher in CD8 T cells those in CD4 T cells. VNN2 T cells were with a higher memory T-cell composition. VNN2 expression was significantly increased after T-cell stimulation. VNN2 T cells had higher levels of GZMB and perforin secretion than VNN2− T cells. Clinically, VNN2 percentages in T cells of patients with SLE were upregulated. Together, these data suggested that VNN2 is expressed in peripheral blood T cells characterized more GZMB and perforin secretion, and increased VNN2 T cells in patients with SLE could reflect altered T-cell functions in vivo.