Intravenous immunoglobulin (IVIg) therapy is widely used to treat autoimmune and infectious disorders. Despite the clinical efficacy of IVIg therapy, its precise immunosuppressive mechanisms remain unclear. Here, we provide evidence that IVIg acts directly on T cells to suppress their activation upon T cell receptor (TCR) ligation. IVIg suppressed the proliferation of murine splenocytes upon stimulation with anti-CD3 antibody and T cell-tropic mitogens. These immunosuppressive effects of IVIg were still intact against purified T cells, and the depletion of naturally-occurring regulatory T cells (nTreg) had no effect on T cell regulatory activity. Instead, we found that IVIg negatively regulated TCR signaling; IVIg co-stimulation impaired hcB degradation, nuclear translocation of the nuclear factor of activated T cells (NEAT), and the activation of mitogen-activated protein kinase (MARK, Erk1/2). These results suggest an additional new immunosuppressive role of IVIg, which acts directly on conventional T cells to suppress the TCR signaling pathway. (C) 2019 Elsevier Inc. All rights reserved.