AbstractDendritic cells (DCs) comprise several subsets that are critically involved in the initiation and regulation of immunity. Clec4A4/DC immunoreceptor 2 (DCIR2) is a C-type lectin receptor (CLR) exclusively expressed on CD8α⁻ conventional DCs (cDCs). However, how Clec4A4 controls immune responses through regulation of the function of CD8α⁻ cDCs remains unclear. Here we show that Clec4A4 is a regulatory receptor for the activation of CD8α⁻ cDCs that impairs inflammation and T-cell immunity. Clec4a4^−/−CD8α⁻ cDCs show enhanced cytokine production and T-cell priming following Toll-like receptor (TLR)-mediated activation. Furthermore, Clec4a4^−/− mice exhibit TLR-mediated hyperinflammation. On antigenic immunization, Clec4a4^−/− mice show not only augmented T-cell responses but also progressive autoimmune pathogenesis. Conversely, Clec4a4^−/− mice exhibit resistance to microbial infection, accompanied by enhanced T-cell responses against microbes. Thus, our findings highlight roles of Clec4A4 in regulation of the function of CD8α⁻ cDCs for control of the magnitude and quality of immune response.