B-lymphocyte hyperactivity in systemic lupus erythematosus (SLE) is T-cell-dependent, and CD4(+) T-cell activation is essential to SLE pathogenesis. However, the mechanism of the deregulation of CD4(+) T cells in SLE is largely unknown. T-cell immunoglobulin and ITIM domain (TIGIT) is a new inhibitory receptor preferentially expressed on activated CD4(+) T cells. Here, we address the role of TIGIT in the pathogenesis of SLE. Our results showed that TIGIT expression on CD4(+) T cells was significantly elevated in patients with SLE and highly correlated with the activity of the disease. TIGIT(+) CD4(+) T cells from both healthy individuals and patients with SLE had a more activated phenotype than TIGIT(-) CD4(+) T cells. In contrast, the activation, proliferation and cytokine production potential of TIGIT(+) CD4(+) T cells were significantly lower than those of TIGIT(-) CD4(+) T cells. Furthermore, activation of the TIGIT pathway by using CD155 could substantially down-regulate the activities of CD4(+) T cells from SLE patients in vitro, and in vivo administration of CD155 resulted in a delayed development of SLE in MRL/lpr mice. TIGIT is a powerful negative regulator of CD4(+) T cells in SLE, which suggests that the TIGIT signalling pathway may be used as a potential therapeutic target for treating this disease.