Background/Purpose: RGC (Response Gene to Complement)-32 is a cell cycle regulator expressed in normal tissues, tumors and a variety of cell lines. RGC-32 plays a role in a variety of pathological processes such as carcinogenesis, metabolic disorders, angiogenesis, atherosclerosis, and autoimmunity. We have shown that RGC-32 exerts a proinflammatory role by promoting Th17 responses in vitro and enhances Th-17 mediated autoimmune diseases in vivo. Th17 pathway has been linked to human lupus including lupus glomerulonephritis (GN). We have shown that in an immune complex mediated model of glomerulonephritis, RGC-32 promoted the Th17 and Th1 dependent proinflammatory responses and the organ specific pathways of renal fibrosis. The expression of RGC-32 in human PBMC and whether RGC-32 plays a role in the Th17 differentiation pathway and in Th17 abnormalities in lupus patients has not yet been investigated. Methods: RGC-32 mRNA expression was first assessed with the BD Biosciences Clontech Autoimmune Disease Profiling Array spotted with cDNA from CD3+, CD19+ and CD14+ cells from 11 lupus patients and 12 controls. PBMC were obtained from 20 patients with lupus and 18 controls. RGC-32 mRNA expression was determined by RT-PCR in purified CD4+ T cells from healthy controls, stimulated under Th0, Th1, Th2, Th17 and Treg conditions. The effect of RGC-32 overexpression and silencing under Th17 conditions was determined by nucleofection. RGC-32 expression in T cells from patients and controls was evaluated by RTPCR, western blot and flow cytometry. Results: Using the Autoimmune Disease Profiling Array, mRNA expression of RGC-32 in healthy controls was highest in CD3+, followed by CD14+ and CD19+ cells. By western blot, RGC-32 protein was constitutively expressed in T cell lysates from normal controls at baseline and upregulated upon TCR stimulation. By intracellular staining RGC-32 was detected in both CD4+ and CD8+ T cells. RGC-32 mRNA expression in T cells from healthy controls was upregulated by TCR stimulation, TGFβ, a known inducer and activator of RGC-32 and by incubation with serum from lupus patients with high anti ds-DNA levels. RGC-32 translocated into nucleus upon TCR stimulation in the presence of TGFβ. In in vitro T cell differentiation assays, RGC-32 upregulation was more robust under Th17 (3.2 ± fold) and Treg (2.6 ± 0.8 fold) vs. Th1 (1.3 ± 0.4 fold) and Th2 (1.8 ± 0.1 fold) conditions. Overexpression or silencing of RGC-32 in CD4+ T cells upregulated, respectively downregulated IL-17A transcript levels and protein secretion. RGC-32 mRNA expression was increased in T cells from lupus patients (1.5 ± 0.38) compared to controls (0.5± 0.2). By flow cytometry, both the proportion (30%± 8 vs 16%± 5) and MFI (200± 65 vs 120±35) of RGC-32+ T cells was significantly higher in lupus T cells vs controls. Conclusion: These results suggest that RGC-32 promotes the differentiation of human Th17 cells. Furthermore, T cells from patients with lupus exhibit increased expression of RGC-32 compared to controls. These data support the idea that RGC-32 signaling may enhance disease expression in SLE by promoting abnormalities in the Th17 pathway and provide a compelling rationale for further investigating the therapeutic potential of blocking RGC-32 in lupus.