CD4^(+)T cells can"help"or"license" conventional type 1 dendritic cells(cDC1s)to induce CD8^(+)cytotoxic T lymphocyte(CTL)anticancer responses,as proven in mouse models.We recently identified cDC1s...CD4^(+)T cells can"help"or"license" conventional type 1 dendritic cells(cDC1s)to induce CD8^(+)cytotoxic T lymphocyte(CTL)anticancer responses,as proven in mouse models.We recently identified cDC1s with a transcriptomic imprint of CD4^(+)T-cell help,specifically in T-cell-infiltrated human cancers,and these cells were associated with a good prognosis and response to PD-1-targeting immunotherapy.Here,we delineate the mechanism of cDC1 licensing by CD4^(+)T cells in humans.Activated CD4^(+)T cells produce IFNβvia the STING pathway,which promotes MHC-I antigen(cross-)presentation by cDC1s and thereby improves their ability to induce CTL anticancer responses.In cooperation with CD40 ligand(L),IFNβalso optimizes the costimulatory and other functions of cDC1s required for CTL response induction.IFN-I-producing CD4^(+)T cells are present in diverse T-cell-infiltrated cancers and likely deliver“help”signals to CTLs locally,according to their transcriptomic profile and colocalization with“helped/licensed”cDCs and tumor-reactive CD8^(+)T cells.In agreement with this scenario,the presence of IFN-I-producing CD4^(+)T cells in the TME is associated with overall survival and the response to PD-1 checkpoint blockade in cancer patients.展开更多
CD4^＋ T-cell help （CD4 help） plays a pivotal role in CD8^＋ T-cell responses against viral infections. However, the role in primary CD8^＋ T-cell responses remains controversial. We evaluated the effects of infecti...CD4^＋ T-cell help （CD4 help） plays a pivotal role in CD8^＋ T-cell responses against viral infections. However, the role in primary CD8^＋ T-cell responses remains controversial. We evaluated the effects of infection route and viral dose on primary CD8^＋ T-cell responses to vaccinia virus （VACV） in MHC class II^-/- mice. CD4 help deficiency diminished the generation of VACV-specific CD8^＋ T cells after intraperitoneal （i.p.） but not after intranasal （i.n.） infection. A large viral dose could not restore normal expansion of VACV-specific CD8^＋ T cells in i.p. infected MHC II-/- mice. In contrast, dependence on CD4 help was observed in i.n. infected MHC II-/- mice when a small viral dose was used. These data suggested that primary CD8~ T-cell responses are less dependent on CD4 help in i.n. infection compared to i.p. infection. Activated CD8~ T cells produced more I FN-y, TNF-a and granzyme B in i.n. infected mice than those in i.p. infected mice, regardless of CD4 help. IL-2 signaling via CD25 was not necessary to drive expansion of VACV-specific CD8~ T cells in i.n. infection, but it was crucial in i.p. infection. VACV-specific CD8^＋ T cells underwent increased apoptosis in the absence of CD4 help, but proliferated normally and had cytotoxic potential, regardless of infection route. Our results indicate that route of infection and viral dose are two determinants for CD4 help dependence, and intranasal infection induces more potent effector CD8^＋ T cells than i.D. infection.展开更多
The clinical success of immune checkpoint therapy(ICT)has produced explosive growth in tumor immunology research because ICT was discovered through basic studies of immune regulation.Much of the current translational ...The clinical success of immune checkpoint therapy(ICT)has produced explosive growth in tumor immunology research because ICT was discovered through basic studies of immune regulation.Much of the current translational efforts are aimed at enhancing ICT by identifying therapeutic targets that synergize with CTLA4 or PD1/PD-L1 blockade and are solidly developed on the basis of currently accepted principles.Expanding these principles through continuous basic research may help broaden translational efforts.With this mindset,we focused this review on three threads of basic research directly relating to mechanisms underlying ICT.Specifically,this review covers three aspects of dendritic cell(DC)biology connected with antitumor immune responses but are not specifically oriented toward therapeutic use.First,we review recent advances in the development of the cDC1 subset of DCs,identifying important features distinguishing these cells from other types of DCs.Second,we review the antigen-processing pathway called cross-presentation,which was discovered in the mid-1970s and remains an enigma.This pathway serves an essential in vivo function unique to cDC1s and may be both a physiologic bottleneck and therapeutic target.Finally,we review the longstanding field of helper cells and the related area of DC licensing,in which CD4 T cells influence the strength or quality of CD8 T cell responses.Each topic is connected with ICT in some manner but is also a fundamental aspect of cell-mediated immunity directed toward intracellular pathogens.展开更多
文摘CD4^(+)T cells can"help"or"license" conventional type 1 dendritic cells(cDC1s)to induce CD8^(+)cytotoxic T lymphocyte(CTL)anticancer responses,as proven in mouse models.We recently identified cDC1s with a transcriptomic imprint of CD4^(+)T-cell help,specifically in T-cell-infiltrated human cancers,and these cells were associated with a good prognosis and response to PD-1-targeting immunotherapy.Here,we delineate the mechanism of cDC1 licensing by CD4^(+)T cells in humans.Activated CD4^(+)T cells produce IFNβvia the STING pathway,which promotes MHC-I antigen(cross-)presentation by cDC1s and thereby improves their ability to induce CTL anticancer responses.In cooperation with CD40 ligand(L),IFNβalso optimizes the costimulatory and other functions of cDC1s required for CTL response induction.IFN-I-producing CD4^(+)T cells are present in diverse T-cell-infiltrated cancers and likely deliver“help”signals to CTLs locally,according to their transcriptomic profile and colocalization with“helped/licensed”cDCs and tumor-reactive CD8^(+)T cells.In agreement with this scenario,the presence of IFN-I-producing CD4^(+)T cells in the TME is associated with overall survival and the response to PD-1 checkpoint blockade in cancer patients.
文摘CD4^＋ T-cell help （CD4 help） plays a pivotal role in CD8^＋ T-cell responses against viral infections. However, the role in primary CD8^＋ T-cell responses remains controversial. We evaluated the effects of infection route and viral dose on primary CD8^＋ T-cell responses to vaccinia virus （VACV） in MHC class II^-/- mice. CD4 help deficiency diminished the generation of VACV-specific CD8^＋ T cells after intraperitoneal （i.p.） but not after intranasal （i.n.） infection. A large viral dose could not restore normal expansion of VACV-specific CD8^＋ T cells in i.p. infected MHC II-/- mice. In contrast, dependence on CD4 help was observed in i.n. infected MHC II-/- mice when a small viral dose was used. These data suggested that primary CD8~ T-cell responses are less dependent on CD4 help in i.n. infection compared to i.p. infection. Activated CD8~ T cells produced more I FN-y, TNF-a and granzyme B in i.n. infected mice than those in i.p. infected mice, regardless of CD4 help. IL-2 signaling via CD25 was not necessary to drive expansion of VACV-specific CD8~ T cells in i.n. infection, but it was crucial in i.p. infection. VACV-specific CD8^＋ T cells underwent increased apoptosis in the absence of CD4 help, but proliferated normally and had cytotoxic potential, regardless of infection route. Our results indicate that route of infection and viral dose are two determinants for CD4 help dependence, and intranasal infection induces more potent effector CD8^＋ T cells than i.D. infection.
文摘The clinical success of immune checkpoint therapy(ICT)has produced explosive growth in tumor immunology research because ICT was discovered through basic studies of immune regulation.Much of the current translational efforts are aimed at enhancing ICT by identifying therapeutic targets that synergize with CTLA4 or PD1/PD-L1 blockade and are solidly developed on the basis of currently accepted principles.Expanding these principles through continuous basic research may help broaden translational efforts.With this mindset,we focused this review on three threads of basic research directly relating to mechanisms underlying ICT.Specifically,this review covers three aspects of dendritic cell(DC)biology connected with antitumor immune responses but are not specifically oriented toward therapeutic use.First,we review recent advances in the development of the cDC1 subset of DCs,identifying important features distinguishing these cells from other types of DCs.Second,we review the antigen-processing pathway called cross-presentation,which was discovered in the mid-1970s and remains an enigma.This pathway serves an essential in vivo function unique to cDC1s and may be both a physiologic bottleneck and therapeutic target.Finally,we review the longstanding field of helper cells and the related area of DC licensing,in which CD4 T cells influence the strength or quality of CD8 T cell responses.Each topic is connected with ICT in some manner but is also a fundamental aspect of cell-mediated immunity directed toward intracellular pathogens.
