Sin1 Controls The Early Stage Of Thymocyte Development Through Regulating PKM2-mediated Glycolysis

T lymphocytes are important for proper adaptive immune responses.T cell precursors are drived from bone marrow and their development begins in the thymus.These precursors proliferate and rearrange their TCRT genes,which endow them with unique antigen specificity in thymus.Thus,analyzing thymocyte development in the thymus is crucial for understanding their functions in immune responses.The target mammalian target of rapamycin(m TOR),is an evolutionarily conserved serine-threonine kinase,which can sense the state of nutrition and energy in the environment and regulate various functions of cells,such as growth,proliferation and development.m TOR functions by forming two different complexes,m TORC1 and m TORC2.m TORC1 mainly plays its role in protein synthesis,while m TORC2 can regulate cell metabolism and survival by controling the phosphorylation of AGC kinases.Stress-activated protein kinase interacting protein 1(Sin1)is an indispensible component of m TORC2,and it has been shown that Sin1 is involved in T cell activation,however,its role in T cell development is still unclear.In this study,Sin1 global knockout mice show a smaller thymus size with lower thymic cellularity.With bone marrow transfer model,we domonstrate that Sin1 knockout in pre-thymic progenitor is the main reason for thymocyte developement blockage at DN3 stage.In order to elucidate the role of Sin1 gene at different stages of thymocyte development,we compared thymocyte development in Lck-Cre dependent knockout mice and CD4-Cre dependent knockout mice.The results show that thymocyte development is blocked at DN3 in Lck-Cre dependent knockout mice,while CD4-Cre dependent knockout mice show normal thymocyte development.Our study suggests that Sin1 plays an important role in the early stage of thymocyte development.Furthermore,we found that Sin1 knockout decreases thymocyte proliferation,downregulates PKM2 expression and nucleotide synthesis.We also elucidates that PPAR-γ of thymocyte can promote PKM2 expression and early stage development.In conclusion,this study shows that Sin1 plays an important role in thymocyte proliferation,and Sin1 regulates DN stage thymocyte glycosis and early development.Our finding broadens the view of the function of m TORC2,and provides a new strategy and potential target for clinical treatment of T cell lymphopenia and T cell lymphoma.