The Role And Mechanism Of PD-1/PD-L1 Pathway In T Lymphocyte And Monocyte In Sepsis

Sepsis is a serious disease with extremely high mortality which is mainly caused by systemic inflammatory response to infection. It is the leading cause of death in critically ill patients. In recent years, scientists'in-depth study of sepsis found that dysfunction is a prominent issue in the pathophysiology of sepsis. During sepsis, the non-specific immune system is over activated, while specific immune system is dysfunctional, It appears to immunosuppression which characterized by reducing T cell reactivity or inducing to a non-reactive state. Immunosuppression is mainly manifested in delayed type hypersensitivity loss, impaired function to remove pathogens, high incidence of secondary infections. Besides the apoptosis of T cell, the dysfunction of mononuclear cell is also an important reason, but its mechanism still remain not clear. This experiment is mainly to study the mechanism of lymphocytes apoptosis and monocytes dysfunction, find out the the key issues of the pathophysiological changes and seek a reasonable therapeutic target.PD-1 (programmed death-1) is a relative molecular mass of 55kDa immunoglobulin superfamily of type I transmembrane glycoprotein. It can bind with PD-L1 or PD-L2 molecules of B7 family. PD-1 can be expressed on T cells, B cells, myeloid cells and thymocytes, suggesting that PD-1 has a wider role in immune regulation. PD-1/PD-L1 pathway play an important role in chronic viral infection, inflammation, tumor immunity, autoimmune diseases, It is suggested that PD-1/PD-L1 pathway may be can become a target to treat these related diseases in the future.This study focused on the function of PD-1/PD-L1 pathway in apoptosis of T lymphocyte and dysfunction of monocytes. In this experiment we found that sepsis patients with significantly higher levels of PD-1 on T lymphocyte surface and significantly higher levels of PD-L1 on monocyte surface than normal, and with a great relevance of different courses. PD-1 and PD-L1 levels of survivo are lower, while PD-1 and PD-L1 levels of non-survivors patients increased significantly. Base on this phenomenon we blocked PD-1/PD-L1 pathway in vitro to detect the apoptosis of T lymphocytes and the function of monocytes. The results showed that anti-PD-Ll blockers can reduce the rate of apoptosis by TNF-a, TCR-induced apoptosis pathway. At the same time, blocking PD-1/PD-L1 pathway can restore the function of monocytes, which showed by the increased inflammatory factor levels and reduced anti-inflammatory factor levels.Mouse model of sepsis (CLP) experiments in vivo further verified the same results. Blocking the PD-1/PD-L1 pathways could improve the CLP mice apoptosis of peripheral blood, spleen, thymus, and lung cell; increase CLP serum levels of proinflammatory factors; reduce the level of anti-inflammatory factor on monocyte. This result suggested that monocytes function has been restored. In addition, it also increased the survival rate of CLP mice. We also found that the expression of PD-1 and PD-L1 reduced significantly in the CLP mice which were cured. Our results further showed that the PD-1/PD-L1 pathway which could reduce the rate of T lymphocyte apoptosis via the death receptor pathway of endogenous and exogenous death receptor pathway. The results showed that PD-1/PD-L1 pathway in sepsis-induced immune suppression process plays an indispensable role. Blocking PD-1/PD-L1 pathway will likely become a potential and new target of the sepsis clinical treatment.