Hyperinflammation, T cells, and endotoxemia

Endotoxemia and sepsis are systemic hyperinflammatory disorders triggered by microbial infection. When infections happen, host cells in the innate immune system quickly act to produce pro-inflammatory cytokines, such as tumor necrosis factor (TNF). Appropriate development of inflammatory responses is essential to protect hosts from microbial infections. However, when inflammatory responses overshoot, collateral organ damages occur in hosts. To avoid this, our immune system is equipped with a variety of mechanisms to downregulate immune responses. To control hyperinflammation in the innate immune system, adaptive immunity was not considered to be involved; because initiating adaptive immune responses takes time. However, others and we demonstrated that T cells, which are components of the adaptive immune system, inhibit hyperinflammation during endotoxemia and sepsis [1-4]. Inhibition of unleashed innate immune responses by T cells was first reported by Kim et al. [1]. The study showed that T cells suppress excessive production of TNFα and IFNγ during poly-I:C-induced endotoxemia [1]. Later on, Guarda et al. reported that T cells suppress IL-1β production by downregulating activities of NLRP1 and NLRP3 inflammasomes. We have recently reported detailed molecular and cellular mechanisms, by which T cells inhibit hyperinflammation during LPS endotoxemia [3, 4]. First critical finding for us was that adoptive transfer of total T cells from naïve mice successfully improved survival of Rag2-/-mice (mice lacking T and B cells) from endotoxemia by decreasing systemic TNF levels [3]. Importantly, transferred T cells did not need to be activated by antigens, suggesting that the T cells protected hosts in an antigen-independent fashion. Indeed, naïve T cells inhibited TNF production by LPS-treated macrophages without any cognate antigens in tissue culture; and the function was demonstrated in 24 hours, which is too early for T cell activation [3]. Importantly, direct contact between T cells and macrophages was essential for the T cell-mediated inhibitory function [3]. Next, we sought receptor(s) mediating the inhibitory mechanism. Because cognate antigens were not involved in the inhibitory mechanism by T cells, the involvement of MHC molecules was ruled out. Instead, interaction between CD40 on macrophages and CD40L on T cells turned out to be critical [3]. CD40 is constitutively expressed in macrophages. On the other hand, Tregs (Foxp3 + CD4 +) in naive mice and Foxp3-CD4 + T cells in LPS-injected mice expressed CD40L; thus, CD4 + T cells do not need to be primed by antigens to express CD40L. Therefore, CD40 on macrophages can be stimulated …