Hyaluronan(HA)production by dendritic cells(DCs)is known to promote antigen presentation and to augment T-cell activation and proliferation.We hypothesized that pericellular HA can function as intercellular‘glue’dir...Hyaluronan(HA)production by dendritic cells(DCs)is known to promote antigen presentation and to augment T-cell activation and proliferation.We hypothesized that pericellular HA can function as intercellular‘glue’directly mediating T cell–DC binding.Using primary human cells,we observed HA-dependent binding between T cells and DCs,which was abrogated upon pre-treatment of the DCs with 4-methylumbelliferone(4-MU),an agent which blocks HA synthesis.Furthermore,T cells regulate HA production by DCs via T cell-derived cytokines in a T helper(Th)subset-specific manner,as demonstrated by the observation that cell-culture supernatants from Th1 but not Th2 clones promote HA production.Similar effects were seen upon the addition of exogenous Th1 cytokines,IL-2,interferon c(IFN-c)and tumor necrosis factor a(TNF-a).The critical factors which determined the extent of DC–T cell binding in this system were the nature of the pre-treatment the DCs received and their capacity to synthesize HA,as T-cell clones which were pre-treated with monensin,added to block cytokine secretion,bound equivalently irrespective of their Th subset.These data support the existence of a feedforward loop wherein T-cell cytokines influence DC production of HA,which in turn affects the extent of DC–T cell binding.We also document the presence of focal deposits of HA at the immune synapse between T-cells and APC and on dendritic processes thought to be important in antigen presentation.These data point to a pivotal role for HA in DC–T cell interactions at the IS.展开更多
Chimeric antigen receptor(CAR)-T-cell therapy has revolutionized cancer treatment.However,its long-term efficacy and broader application are limited because of its antigen insensitivity,poor persistence,and T-cell exh...Chimeric antigen receptor(CAR)-T-cell therapy has revolutionized cancer treatment.However,its long-term efficacy and broader application are limited because of its antigen insensitivity,poor persistence,and T-cell exhaustion.A recent study published by Xu et al.revealed a novel CAR engineering strategy that overcomes these difficulties by incorporating a modified CD3εintracellular domain,EB6I,into the conventional CAR structure[1].This modification enhances antigen sensitivity and sustains the cytotoxic activity of CAR-T cells,demonstrating promising efficacy in treating various tumor models,including solid tumors and hematological malignancies.This strategy could be applied to different CAR types,including 28Z and BBZ CARs,underscoring its transformative potential in overcoming current limitations and broadening the therapeutic scope of CAR-T-cell immunotherapy.展开更多
基金This work was supported by grants from the NIH(DK46635,HL18645 and DK53004)the JDRF(The Center for Translational Research at BRI)PLB is supported by NIH K-08 grant DK080178-01 and an NIH LRP grant.The authors would like to thank Nathan Standifer and Michael Kinsella for their helpful comments and Tuan Nguyen for tissue processing.
文摘Hyaluronan(HA)production by dendritic cells(DCs)is known to promote antigen presentation and to augment T-cell activation and proliferation.We hypothesized that pericellular HA can function as intercellular‘glue’directly mediating T cell–DC binding.Using primary human cells,we observed HA-dependent binding between T cells and DCs,which was abrogated upon pre-treatment of the DCs with 4-methylumbelliferone(4-MU),an agent which blocks HA synthesis.Furthermore,T cells regulate HA production by DCs via T cell-derived cytokines in a T helper(Th)subset-specific manner,as demonstrated by the observation that cell-culture supernatants from Th1 but not Th2 clones promote HA production.Similar effects were seen upon the addition of exogenous Th1 cytokines,IL-2,interferon c(IFN-c)and tumor necrosis factor a(TNF-a).The critical factors which determined the extent of DC–T cell binding in this system were the nature of the pre-treatment the DCs received and their capacity to synthesize HA,as T-cell clones which were pre-treated with monensin,added to block cytokine secretion,bound equivalently irrespective of their Th subset.These data support the existence of a feedforward loop wherein T-cell cytokines influence DC production of HA,which in turn affects the extent of DC–T cell binding.We also document the presence of focal deposits of HA at the immune synapse between T-cells and APC and on dendritic processes thought to be important in antigen presentation.These data point to a pivotal role for HA in DC–T cell interactions at the IS.
基金supported by grants from the National Natural Science Foundation of China(32350007 and 32441096 to LL).
文摘Chimeric antigen receptor(CAR)-T-cell therapy has revolutionized cancer treatment.However,its long-term efficacy and broader application are limited because of its antigen insensitivity,poor persistence,and T-cell exhaustion.A recent study published by Xu et al.revealed a novel CAR engineering strategy that overcomes these difficulties by incorporating a modified CD3εintracellular domain,EB6I,into the conventional CAR structure[1].This modification enhances antigen sensitivity and sustains the cytotoxic activity of CAR-T cells,demonstrating promising efficacy in treating various tumor models,including solid tumors and hematological malignancies.This strategy could be applied to different CAR types,including 28Z and BBZ CARs,underscoring its transformative potential in overcoming current limitations and broadening the therapeutic scope of CAR-T-cell immunotherapy.
