In exploring persistent infections and malignancies, a distinctive subgroup of CD8^(+) T cells, progenitor exhausted CD8^(+) T(Tpex) cells, has been identified. These Tpex cells are notable for their remarkable self-r...In exploring persistent infections and malignancies, a distinctive subgroup of CD8^(+) T cells, progenitor exhausted CD8^(+) T(Tpex) cells, has been identified. These Tpex cells are notable for their remarkable self-renewal and rapid proliferation abilities. Recent strides in immunotherapy have demonstrated that Tpex cells expand and differentiate into responsive exhausted CD8^(+) T cells, thus underscoring their critical role in the immunotherapeutic retort. Clinical examinations have further clarified a robust positive correlation between the proportional abundance of Tpex cells and enhanced clinical prognosis. Tpex cells have found noteworthy applications in the formulation of inventive immunotherapeutic approaches against tumors. This review describes the functions of Tpex cells in the tumor milieu, particularly their potential utility in tumor immunotherapy. Precisely directing Tpex cells may be essential to achieving successful outcomes in immunotherapy against tumors.展开更多
Tcf-1(encoded by Tcf7)not only plays critical roles in promoting T cell development and differentiation but also has been identified as a tumor suppressor involved in preventing T cell malignancy.However,the comprehen...Tcf-1(encoded by Tcf7)not only plays critical roles in promoting T cell development and differentiation but also has been identified as a tumor suppressor involved in preventing T cell malignancy.However,the comprehensive mechanisms of Tcf-1 involved in T cell transformation remain poorly understood.In this study,Tcf7^(fl/fl)mice were crossed with Vav-cre,Lck-cre,or Cd4-cre mice to delete Tcf-1 conditionally at the beginning of the HSC,DN2-DN3,or DP stage,respectively.The defective T cell development phenotypes became gradually less severe as the deletion stage became more advanced in distinct mouse models.Interestingly,consistent with Tcf7^(-/-)mice,Tcf^(fl/fl)Vav-cre mice developed aggressive T cell lymphoma within 45 weeks,but no tumors were generated in Tcf7^(fl/fl)Lck-cre or Tcf^(fl/fl)CdA-cre mice.Single-cell RNA-seq(ScRNA-seq)indicated that ablation of Tcf-1 at distinct phases can subdivide DN1 cells into three clusters(C1,C2,and C3)and DN2-DN3 cells into three clusters(C4,C5,and C6).Moreover,Tcf-1 deficiency redirects bifurcation among divergent cell fates,and clusters C1 and C4 exhibit high potential for leukemic transformation.Mechanistically,we found that Tcf-1 directly binds and mediates chromatin accessibility for both typical T cell regulators and proto-oncogenes#including Myb,Mycn,Runxl,and Lyl1 in the DN1 phase and Lefb ld2,Dtxb Fyn,Bclllb,and Zfp36l2 in the DN2-DN3 phase.The aberrant expression of these genes due to Tcf-1 deficiency in very early T cells contributes to subsequent tumorigenesis.Thus,we demonstrated that Tcf-1 plays stage-specific roles in regulating early thymocyte development and transformation,providing new insights and evidence for clinical trials on T-ALL leukemia.展开更多
基金supported by grants from the National Natural Science Foundation of China (Grant No. 32270955)the Jiangsu Provincial Medical Key Discipline (Grant No. YXZDXK202236)+1 种基金the Key Project of Jiangsu Provincial Health Commission (Grant No. K2023069)the Science and Technology Support Plan (Social Development) Project of Changzhou (Grant No. CE20235058)。
文摘In exploring persistent infections and malignancies, a distinctive subgroup of CD8^(+) T cells, progenitor exhausted CD8^(+) T(Tpex) cells, has been identified. These Tpex cells are notable for their remarkable self-renewal and rapid proliferation abilities. Recent strides in immunotherapy have demonstrated that Tpex cells expand and differentiate into responsive exhausted CD8^(+) T cells, thus underscoring their critical role in the immunotherapeutic retort. Clinical examinations have further clarified a robust positive correlation between the proportional abundance of Tpex cells and enhanced clinical prognosis. Tpex cells have found noteworthy applications in the formulation of inventive immunotherapeutic approaches against tumors. This review describes the functions of Tpex cells in the tumor milieu, particularly their potential utility in tumor immunotherapy. Precisely directing Tpex cells may be essential to achieving successful outcomes in immunotherapy against tumors.
基金supported by the National Key R&D Program of China(2017YFA0104401)the National Natural Science Foundation of China(31630038,31970831,and 31571522)the Project for Extramural Scientists of State Key Laboratory of Agrobiotechnology from China Agricultural University(2019SKLAB6-6&2019SKLAB6-7).
文摘Tcf-1(encoded by Tcf7)not only plays critical roles in promoting T cell development and differentiation but also has been identified as a tumor suppressor involved in preventing T cell malignancy.However,the comprehensive mechanisms of Tcf-1 involved in T cell transformation remain poorly understood.In this study,Tcf7^(fl/fl)mice were crossed with Vav-cre,Lck-cre,or Cd4-cre mice to delete Tcf-1 conditionally at the beginning of the HSC,DN2-DN3,or DP stage,respectively.The defective T cell development phenotypes became gradually less severe as the deletion stage became more advanced in distinct mouse models.Interestingly,consistent with Tcf7^(-/-)mice,Tcf^(fl/fl)Vav-cre mice developed aggressive T cell lymphoma within 45 weeks,but no tumors were generated in Tcf7^(fl/fl)Lck-cre or Tcf^(fl/fl)CdA-cre mice.Single-cell RNA-seq(ScRNA-seq)indicated that ablation of Tcf-1 at distinct phases can subdivide DN1 cells into three clusters(C1,C2,and C3)and DN2-DN3 cells into three clusters(C4,C5,and C6).Moreover,Tcf-1 deficiency redirects bifurcation among divergent cell fates,and clusters C1 and C4 exhibit high potential for leukemic transformation.Mechanistically,we found that Tcf-1 directly binds and mediates chromatin accessibility for both typical T cell regulators and proto-oncogenes#including Myb,Mycn,Runxl,and Lyl1 in the DN1 phase and Lefb ld2,Dtxb Fyn,Bclllb,and Zfp36l2 in the DN2-DN3 phase.The aberrant expression of these genes due to Tcf-1 deficiency in very early T cells contributes to subsequent tumorigenesis.Thus,we demonstrated that Tcf-1 plays stage-specific roles in regulating early thymocyte development and transformation,providing new insights and evidence for clinical trials on T-ALL leukemia.
