Thymic involution during aging is a major cause of decreased T-cell production and reduced immunity.Here,we show that the loss of CD147 on T cells prevents thymic senescence,resulting in slowed shrinkage of the thymus...Thymic involution during aging is a major cause of decreased T-cell production and reduced immunity.Here,we show that the loss of CD147 on T cells prevents thymic senescence,resulting in slowed shrinkage of the thymus with age and increased production of naive T cells.This phenotype is the result of slowing of the epithelial-mesenchymal transition(EMT)process in thymic epithelial cells(TECs),which eventually leads to reduced adipocyte accumulation.In an in vitro coculture system,we found that TGFβ is an important factor in the EMT process in TECs and that it can reduce the expression of E-cadherin through p-5mad2/FoxC2 signaling.Moreover,CD147 on T cells can accelerate the decline in E-cadherin expression by interacting with Annexin A2 on TECs.In the presence of TGFβ,Annexin A2 and E-cadherin colocalize on TECs.However,CD147 on T cells competitively binds to Annexin A2 on TECs,leading to the isolation of E-cadherin.Then,the isolated E-cadherin is easily phosphorylated by phosphorylated Src kinase,the phosphorylation of which was induced by TGFβ,and finally,p-E-cadherin is degraded.Thus,in the thymus,the interaction between T ceils and TECs contributes to thymic involution with age.In this study,we illuminate the mechanism underlying the triggering of the EMT process in TECs and show that inhibiting TGFβ and/or CD147 may serve as a strategy to hinder age-related thymic involution.展开更多
基金supported by grants from the National Key Research and Development Program of China(2018YFA0109000)National Natural Science Foundation of China(31800756).
文摘Thymic involution during aging is a major cause of decreased T-cell production and reduced immunity.Here,we show that the loss of CD147 on T cells prevents thymic senescence,resulting in slowed shrinkage of the thymus with age and increased production of naive T cells.This phenotype is the result of slowing of the epithelial-mesenchymal transition(EMT)process in thymic epithelial cells(TECs),which eventually leads to reduced adipocyte accumulation.In an in vitro coculture system,we found that TGFβ is an important factor in the EMT process in TECs and that it can reduce the expression of E-cadherin through p-5mad2/FoxC2 signaling.Moreover,CD147 on T cells can accelerate the decline in E-cadherin expression by interacting with Annexin A2 on TECs.In the presence of TGFβ,Annexin A2 and E-cadherin colocalize on TECs.However,CD147 on T cells competitively binds to Annexin A2 on TECs,leading to the isolation of E-cadherin.Then,the isolated E-cadherin is easily phosphorylated by phosphorylated Src kinase,the phosphorylation of which was induced by TGFβ,and finally,p-E-cadherin is degraded.Thus,in the thymus,the interaction between T ceils and TECs contributes to thymic involution with age.In this study,we illuminate the mechanism underlying the triggering of the EMT process in TECs and show that inhibiting TGFβ and/or CD147 may serve as a strategy to hinder age-related thymic involution.
