Regulatory Mechanisms And Therapeutic Strategies Of T Cells In Inflammatory Immune Response

Inflammation is the body’s defense response to stimulation,manifested as red,swelling,heat,pain and dysfunction.Inflammation can be divided into autoimmune inflammation and infectious inflammation.In general,inflammation is beneficial,is the body’s automatic defense response,but sometimes inflammation is also harmful,will attack the body’s own organization,etc..T cells play an important role in the inflammatory response.Inflammation is accompanied by massive infiltration of T cells.Now,for the treatment of inflammation,more is now directed to T cells as effector cells.However,in practical application,it can be found that the inhibition of T cells can inhibit inflammation effect to some extent,but the inflammatory response will continue.So we focused our attention on antigen presenting cells.We established models of autoimmune inflammation experimental autoimmune encephalomyelitis model,and infectious inflammation fulminant hepatic failure model induced by P.acnes,to analyze the effect of antigen presenting cells on T cells.In the autoimmune inflammatory model EAE,microglia are the innate immune cells of the central nervous system with antigen presentation.Microglial activation plays an important role.Here we show that administration of 18β-glycyrrhetinic acid（GRA）significantly suppresses disease severity of experimental autoimmune encephalomyelitis（EAE）in C57BL/6 mice.We found that GRA did not affect the proportion and number of T cell subsets,including Th1 and Th17,Treg and GM^-CSF⁺pathogenic T cells.At the same time by using the adoptive transfer model,it shows that GRA treatment does not alter the pathogenicity of pathogenic T cells,but affects the function process of pathogenic T cells,namely blocking pathogenic T cells from the peripheral to the migration and invasion of CNS.Further studies showed that GRA could inhibit the migration of immune cells such as T cells into CNS,by inhibiting the expression of chemokines in CNS and increasing the expression of chemokine receptors in peripheral lymphocytes.The results showed that GRA had no effect on the genes controlling inflammation in macrophages,and had no effect on the chemotaxis of macrophages.GRA inhibits microglia activation via MAPK signaling pathway.In addition,GRA treatment promoted remyelination in the CNS of EAE mice.The induced remyelination can be mediated by the overcome of inflammation-induced blockade of brain-derived neurotrophic factor expression in microglia,as well as enhancing oligodendrocyte precursor cell proliferation.In an infectious inflammatory model fulminant hepatic failure induced by P.acne,dendritic cells,as the most powerful antigen presenting cells,play an important role We found that inhibition of Heat shock protein 90（Hsp90）with inhibitor AUY922 could reduce the mortality of fulminant hepatic failure in mice.We found that inhibit Hsp90can reduce the mortality of fulminant hepatic failure in mice,significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels,inhibit the formation of abnormal surface nodules in liver,reduce the lymphocytes in mouse liver infiltration,reduce the expression of Fas L.Inhibition of Hsp90 could decrease the migration of CD4⁺T cells to the liver and inhibit the activation of DC cells,and form a group of DC with CD11c⁺MHCII^hiCD80^loCD86^lo.It was found that the direct interaction between Enhancer of Zeste Homolog 2（Ezh2）and Hsp90.Hsp90 specific inhibitor AUY922 can effectively reduce the expression of Ezh2 without affecting the level of histone H3K27me3.Inhibition of Ezh2 by small molecule inhibitors DZNep and GSK126 can effectively alleviate FHF.It has been proved that both in autoimmune inflammation and infectious inflammation,Regulating the antigen-presenting cells can regulate the T cell response.To study the regulation mechanism of T cell effect and explore the strategy of intervention has broad application prospects.