Generation and maintenance of antigen-specific effector and memory T cells are central events in immune responses against infections.We show that TNF receptor-associated factor 2(TRAF2)maintains a survival signaling a...Generation and maintenance of antigen-specific effector and memory T cells are central events in immune responses against infections.We show that TNF receptor-associated factor 2(TRAF2)maintains a survival signaling axis in effector and memory CD8 T cells required for immune responses against infections.This signaling axis involves activation of Tpl2 and its downstream kinase ERK by NF-κB-inducing kinase(NIK)and degradation of the proapoptotic factor Bim.NIK mediates Tpl2 activation by stimulating the phosphorylation and degradation of the Tpl2 inhibitor p105.Interestingly,while NIK is required for Tpl2-ERK signaling under normal conditions,uncontrolled NIK activation due to loss of its negative regulator,TRAF2,causes constitutive degradation of p105 and Tpl2,leading to severe defects in ERK activation and effector/memory CD8 T cell survival.Thus,TRAF2 controls a previously unappreciated signaling axis mediating effector/memory CD8 T cell survival and protective immunity.展开更多
B cells home to the lymph nodes(LNs)via high endothelial venules(HEVs)under the guidance of chemokines,particularly CXCL13.However,as CXCL13 is not directly made in HEVs,the molecular mechanism mediating B-cell homing...B cells home to the lymph nodes(LNs)via high endothelial venules(HEVs)under the guidance of chemokines,particularly CXCL13.However,as CXCL13 is not directly made in HEVs,the molecular mechanism mediating B-cell homing to LNs has remained unclear.We show here that nuclear factor(NF)-κB-inducing kinase(NIK),a kinase mediating activation of the noncanonical NF-κB pathway,functions in lymphatic endothelial cells(LECs)to regulate B-cell homing to LNs.LEC-conditional deletion of NIK in mice did not affect the integrity or global function of lymphatic vessels but caused a severe reduction in the frequency of B cells in LNs.The LEC-specific NIK deficiency did not affect the survival of B cells or the frequency of B cells in the spleen.B-cell adoptive transfer studies revealed that the LEC-specific NIK deletion impairs the ability of LNs to recruit B cells.We further show that NIK mediates expression of the chemokines CXCL13 and CCL19 in LECs.Although CCL19 is also expressed in blood endothelial cells(BECs),CXCL13 is not produced in BECs.These results suggest that NIK regulates naive B-cell homing to LNs via mediating production of the B-cell homing chemokine CXCL13 in LECs.展开更多
基金This study was supported by grants from the National Institutes of Health(AI64639 and GM84459)the core facilities of MD Anderson Cancer Center are supported by the NIH/NCI Cancer Center Support Grant(CCSG)P30CA016672.
文摘Generation and maintenance of antigen-specific effector and memory T cells are central events in immune responses against infections.We show that TNF receptor-associated factor 2(TRAF2)maintains a survival signaling axis in effector and memory CD8 T cells required for immune responses against infections.This signaling axis involves activation of Tpl2 and its downstream kinase ERK by NF-κB-inducing kinase(NIK)and degradation of the proapoptotic factor Bim.NIK mediates Tpl2 activation by stimulating the phosphorylation and degradation of the Tpl2 inhibitor p105.Interestingly,while NIK is required for Tpl2-ERK signaling under normal conditions,uncontrolled NIK activation due to loss of its negative regulator,TRAF2,causes constitutive degradation of p105 and Tpl2,leading to severe defects in ERK activation and effector/memory CD8 T cell survival.Thus,TRAF2 controls a previously unappreciated signaling axis mediating effector/memory CD8 T cell survival and protective immunity.
基金by grants from the National Institutes of Health(GM84459,AI057555,AI104519 and AI64639)This study also used the NIH/NCI-supported resources under award number P30CA016672 at The MD Anderson Cancer CenterSZ was supported by a scholarship from the China Scholarship Council(CSC)under the Grant CSC 201506210393.
文摘B cells home to the lymph nodes(LNs)via high endothelial venules(HEVs)under the guidance of chemokines,particularly CXCL13.However,as CXCL13 is not directly made in HEVs,the molecular mechanism mediating B-cell homing to LNs has remained unclear.We show here that nuclear factor(NF)-κB-inducing kinase(NIK),a kinase mediating activation of the noncanonical NF-κB pathway,functions in lymphatic endothelial cells(LECs)to regulate B-cell homing to LNs.LEC-conditional deletion of NIK in mice did not affect the integrity or global function of lymphatic vessels but caused a severe reduction in the frequency of B cells in LNs.The LEC-specific NIK deficiency did not affect the survival of B cells or the frequency of B cells in the spleen.B-cell adoptive transfer studies revealed that the LEC-specific NIK deletion impairs the ability of LNs to recruit B cells.We further show that NIK mediates expression of the chemokines CXCL13 and CCL19 in LECs.Although CCL19 is also expressed in blood endothelial cells(BECs),CXCL13 is not produced in BECs.These results suggest that NIK regulates naive B-cell homing to LNs via mediating production of the B-cell homing chemokine CXCL13 in LECs.
