Innate immunity has a protective role against pathogen infection in very early stages of infection. However, prolonged activation of innate immunity leads to hyperinflammation, which induces collateral damage of host tissues. We have demonstrated that antigen-unprimed T cells control hyperinflamamtion in innate immunity. This is new, because T cells are not supposed to be involved in controlling acute hyperinflammation due to the time needed to activate T cells. This controlling by T cells can be achieved by direct interaction between T cells and macrophages, and by tracking IL-10 upregulation and TNF downregulation via intracellular osteopontin (iOPN) (PNAS 2014), which plays a role in anchoring molecules for several cytosolic molecules under the pattern recognition receptors signaling (J. Immunol. 2011). We further demonstrated that T-macrophage interaction is initiated by secreted osteopontin (sOPN) from macrophages, which attracts antigen-unprimed T cells with an integrin αv receptor on the T cell’s surface (J. Immunol. 2015). These findings have clarified how antigen-unprimed T cells actually play an important role in controlling overreactions in our immune system. Furthermore, while OPN generally induces pro-inflammatory responses, these findings have demonstrated an anti-inflammatory response by OPN in endotoxemia.