Objective Since most reports on bystander effect have been only concerned with radiation-induced damage, the present paper aimed at disclosing whether low dose radiation could induce a stimulatory or beneficial bystan...Objective Since most reports on bystander effect have been only concerned with radiation-induced damage, the present paper aimed at disclosing whether low dose radiation could induce a stimulatory or beneficial bystander effect. Methods A co-culture system containing irradiated antigen presenting cells (J774A.1) and unirradiated T lymphocytes (EL-4) was established to observe the effect of J774A.1 cells exposed to both low and high doses of X-rays on the unirradiated EL-4 cells. Incorporation of 3H-TdR was used to assess the proliferation of the EL-4 cells, expression of CD80/86 and CD48 on J774A.1 cells was measured with immunohistochemistry and flow cytometry, respectively. NO release from J774A.1 cells was estimated with nitrate reduction method. Results Low dose-irradiated J774A.1 cells could stimulate the proliferation of the unirradiated EL-4 cells while the high dose-irradiated J774A.1 cells exerted an inhibitory effect on the proliferation of the unirradiated EL-4 cells. Preliminary mechanistic studies illustrated that the differential changes in CD48 expression and NO production by the irradiated J774A.1 cells after high and low dose radiation might be important factors underlying the differential bystander effect elicited by different doses of radiation. Conclusion Stimulatory bystander effect can be induced in immune cells by low dose radiation.展开更多
The adaptive immune response relies on specific apoptotic programs to maintain homeostasis.Conventional effector T cell(Tcon)expansion is constrained by both forkhead box P3(FOXP3)^(+)-regulatory T cells(Tregs)and res...The adaptive immune response relies on specific apoptotic programs to maintain homeostasis.Conventional effector T cell(Tcon)expansion is constrained by both forkhead box P3(FOXP3)^(+)-regulatory T cells(Tregs)and restimulation-induced cell death(RICD),a proprlocidal apoptosis pathway triggered by repeated stimulation through the T-cell receptor(TCR).Constitutive FOXP3 expression protects Tregs from RICD by suppressing SLAM-associated protein(SAP),a key adaptor protein that amplifies TCR signaling strength.The role of transient FOXP3 induction in activated human CD4 and CD8 Tcons remains unresolved,but its expression is inversely correlated with acquired RICD sensitivity.Here,we describe a novel role for FOXP3 In protecting human Tcons from premature RICD during expansion.Unlike FOXP3-mediated protection from RICD in Tregs,FOXP3 protects Tcons through a distinct mechanism requiring de novo transcription that does not require SAP suppression.Transcriptome profiling and functional analyses of expanding Tcons revealed that FOXP3 enhances expression of the SLAM family receptor CD48,which in turn sustains basal autophagy and suppresses pro-apoptotic p53 signaling.Both CD48 and FOXP3 expression reduced p53 accumulation upon TCR restimulation.Furthermore,silencing FOXP3 expression or blocking CD48 decreased the mitochondrial membrane potential in expanding Tcons with a concomitant reduction in basal autophagy.Our findings suggest that FOXP3 governs a distinct transcriptional program in early-stage effector Tcons that maintains RICD resistance via CD48-dependent protective autophagy and p53 suppression.展开更多
基金This work was supported by grants from NSFC (No. 39270207, No. 39570188).
文摘Objective Since most reports on bystander effect have been only concerned with radiation-induced damage, the present paper aimed at disclosing whether low dose radiation could induce a stimulatory or beneficial bystander effect. Methods A co-culture system containing irradiated antigen presenting cells (J774A.1) and unirradiated T lymphocytes (EL-4) was established to observe the effect of J774A.1 cells exposed to both low and high doses of X-rays on the unirradiated EL-4 cells. Incorporation of 3H-TdR was used to assess the proliferation of the EL-4 cells, expression of CD80/86 and CD48 on J774A.1 cells was measured with immunohistochemistry and flow cytometry, respectively. NO release from J774A.1 cells was estimated with nitrate reduction method. Results Low dose-irradiated J774A.1 cells could stimulate the proliferation of the unirradiated EL-4 cells while the high dose-irradiated J774A.1 cells exerted an inhibitory effect on the proliferation of the unirradiated EL-4 cells. Preliminary mechanistic studies illustrated that the differential changes in CD48 expression and NO production by the irradiated J774A.1 cells after high and low dose radiation might be important factors underlying the differential bystander effect elicited by different doses of radiation. Conclusion Stimulatory bystander effect can be induced in immune cells by low dose radiation.
基金This work was funded by grants from the National Institutes of Health (1R01GM105821) and Uniformed Services University.
文摘The adaptive immune response relies on specific apoptotic programs to maintain homeostasis.Conventional effector T cell(Tcon)expansion is constrained by both forkhead box P3(FOXP3)^(+)-regulatory T cells(Tregs)and restimulation-induced cell death(RICD),a proprlocidal apoptosis pathway triggered by repeated stimulation through the T-cell receptor(TCR).Constitutive FOXP3 expression protects Tregs from RICD by suppressing SLAM-associated protein(SAP),a key adaptor protein that amplifies TCR signaling strength.The role of transient FOXP3 induction in activated human CD4 and CD8 Tcons remains unresolved,but its expression is inversely correlated with acquired RICD sensitivity.Here,we describe a novel role for FOXP3 In protecting human Tcons from premature RICD during expansion.Unlike FOXP3-mediated protection from RICD in Tregs,FOXP3 protects Tcons through a distinct mechanism requiring de novo transcription that does not require SAP suppression.Transcriptome profiling and functional analyses of expanding Tcons revealed that FOXP3 enhances expression of the SLAM family receptor CD48,which in turn sustains basal autophagy and suppresses pro-apoptotic p53 signaling.Both CD48 and FOXP3 expression reduced p53 accumulation upon TCR restimulation.Furthermore,silencing FOXP3 expression or blocking CD48 decreased the mitochondrial membrane potential in expanding Tcons with a concomitant reduction in basal autophagy.Our findings suggest that FOXP3 governs a distinct transcriptional program in early-stage effector Tcons that maintains RICD resistance via CD48-dependent protective autophagy and p53 suppression.
