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Project description:The immune system undergoes a progressive functional remodeling with age. Understanding how age bias shapes antitumor immunity is essential in designing effective immunotherapies, especially for pediatric patients. Here, we explore antitumor CD8+ T cell responses generated in young (prepubescent) and adult (presenescent) mice. Using an MHCI-deficient tumor model, we observed that tumor-reactive CD8+ T cells expanded in young tumor-bearing (TB) mice acquired a terminally differentiated phenotype characterized by overexpression of inhibitory receptors and the transcription factor Tox1. Furthermore, tumor-infiltrating CD8+ T cells from young tumors yielded a poor cytokine response compared with CD8+ T cells infiltrating adult tumors. Young migratory dendritic cells (migDCs) from the draining lymph nodes (dLNs), and mononuclear phagocytic cells (MPCs) infiltrating young tumors, were more competent in capturing and cross-presenting tumor antigen, leading to enhanced priming of CD8+ T cells in dLNs and their subsequent terminal differentiation in the tumors. Single-cell transcriptional profiling of tumor-infiltrating MPCs demonstrated that young MPCs are polarized toward an inflammatory, effector phenotype. Consistent with our observations in young versus adult TB mice, analysis of immune infiltrates from pediatric solid tumors showed a correlation between tumor-infiltrating CD8+ T cells with an exhaustion phenotype and the frequency of PD-L1-expressing monocytes/macrophages. Collectively, these data indicate that a young tissue microenvironment contributes to the generation of an immune response skewed toward a less pliable terminal effector state, thus narrowing the window for immunotherapeutic interventions.
| S-EPMC8990347 | biostudies-literature
Project description:The immune system undergoes a progressive functional remodeling with age, polarizing the immune responses toward a “killer” or “healer” phenotype. Understanding how the age bias shapes anti-tumor immunity is essential in designing effective immunotherapies. In this manuscript we explore the anti-tumor CD8+ T cell responses generated in young (prepubescent) and adult (pre-senescent) mice. Using an MHCI-deficient, trackable tumor model, we observed that tumor reactive CD8+ T cells that expanded in young tumor-bearing (TB) mice acquired a terminally differentiated phenotype characterized by overexpression of inhibitory receptors and the transcription factor Tox1. Furthermore, tumor infiltrating CD8+ T cells from young tumors yielded a poor cytokine response compared to CD8+ T cells infiltrating adult tumors. Young migratory dendritic cells (migDC) and mononuclear phagocytic cells (MPCs) infiltrating young tumors were more competent in capturing and cross-presenting tumor antigen, leading to enhanced priming of CD8+ T cells in the draining lymph nodes (dLNs), and their subsequent terminal differentiation in the tumors. Notably, single-cell transcriptional profiling of tumor infiltrating MPCs revealed that young MPCs are polarized toward an inflammatory, effector phenotype. Consistent with our observations in young vs adult TB mice, analysis of immune infiltrates from pediatric solid tumors revealed a significant correlation between tumor-infiltrating CD8+ T cells with an exhaustion phenotype and the frequency of PD-L1-expressing phagocytic cells. Collectively, these data indicate that the young microenvironment of an actively developing tissue contributes to the generation of an immune response skewed toward a terminal effector state, thus narrowing the window for immunotherapeutic interventions.
2022-02-28 | GSE188388 | GEO
Project description:The immune system undergoes a progressive functional remodeling with age, polarizing the immune responses toward a “killer” or “healer” phenotype. Understanding how the age bias shapes anti-tumor immunity is essential in designing effective immunotherapies. In this manuscript we explore the anti-tumor CD8+ T cell responses generated in young (prepubescent) and adult (pre-senescent) mice. Using an MHCI-deficient, trackable tumor model, we observed that tumor reactive CD8+ T cells that expanded in young tumor-bearing (TB) mice acquired a terminally differentiated phenotype characterized by overexpression of inhibitory receptors and the transcription factor Tox1. Furthermore, tumor infiltrating CD8+ T cells from young tumors yielded a poor cytokine response compared to CD8+ T cells infiltrating adult tumors. Young migratory dendritic cells (migDC) and mononuclear phagocytic cells (MPCs) infiltrating young tumors were more competent in capturing and cross-presenting tumor antigen, leading to enhanced priming of CD8+ T cells in the draining lymph nodes (dLNs), and their subsequent terminal differentiation in the tumors. Notably, single-cell transcriptional profiling of tumor infiltrating MPCs revealed that young MPCs are polarized toward an inflammatory, effector phenotype. Consistent with our observations in young vs adult TB mice, analysis of immune infiltrates from pediatric solid tumors revealed a significant correlation between tumor-infiltrating CD8+ T cells with an exhaustion phenotype and the frequency of PD-L1-expressing phagocytic cells. Collectively, these data indicate that the young microenvironment of an actively developing tissue contributes to the generation of an immune response skewed toward a terminal effector state, thus narrowing the window for immunotherapeutic interventions.
2022-02-28 | GSE188387 | GEO
Project description:Antigen cross-presentation in young tumor-bearing hosts promotes CD8 T cell terminal differentiation
| PRJNA778706 | ENA
Project description:Antigen cross-presentation in young tumor-bearing hosts promotes CD8 T cell terminal differentiation [WGBS]
| PRJNA778717 | ENA
Project description:Antigen cross-presentation in young tumor-bearing hosts promotes CD8 T cell terminal differentiation [gene expression]
| PRJNA778718 | ENA
Project description:Virus-specific CD8(+) T cells (T(CD8+)) are initially triggered by peptide-MHC Class I complexes on the surface of professional antigen presenting cells (pAPC). Peptide-MHC complexes are produced by two spatially distinct pathways during virus infection. Endogenous antigens synthesized within virus-infected pAPC are presented via the direct-presentation pathway. Many viruses have developed strategies to subvert direct presentation. When direct presentation is blocked, the cross-presentation pathway, in which antigen is transferred from virus-infected cells to uninfected pAPC, is thought to compensate and allow the generation of effector T(CD8+). Direct presentation of vaccinia virus (VACV) antigens driven by late promoters does not occur, as an abortive infection of pAPC prevents production of these late antigens. This lack of direct presentation results in a greatly diminished or ablated T(CD8+) response to late antigens. We demonstrate that late poxvirus antigens do not enter the cross-presentation pathway, even when identical antigens driven by early promoters access this pathway efficiently. The mechanism mediating this novel means of viral modulation of antigen presentation involves the sequestration of late antigens within virus factories. Early antigens and cellular antigens are cross-presented from virus-infected cells, as are late antigens that are targeted to compartments outside of the virus factories. This virus-mediated blockade specifically targets the cross-presentation pathway, since late antigen that is not cross-presented efficiently enters the MHC Class II presentation pathway. These data are the first to describe an evasion mechanism employed by pathogens to prevent entry into the cross-presentation pathway. In the absence of direct presentation, this evasion mechanism leads to a complete ablation of the T(CD8+) response and a potential replicative advantage for the virus. Such mechanisms of viral modulation of antigen presentation must also be taken into account during the rational design of antiviral vaccines.
| S-EPMC2680035 | biostudies-other
Project description:Antigen cross-presentation by dendritic cells (DC) stimulates cytotoxic T cell activation to promote immunity to intracellular pathogens, viruses and cancer. Phagocytosed antigens generate potent T cell responses, but the signalling and trafficking pathways regulating their cross-presentation are unclear. Here, we show that ablation of the store-operated-Ca2+-entry regulator STIM1 in mouse myeloid cells impairs cross-presentation and DC migration in vivo and in vitro. Stim1 ablation reduces Ca2+ signals, cross-presentation, and chemotaxis in mouse bone-marrow-derived DCs without altering cell differentiation, maturation or phagocytic capacity. Phagosomal pH homoeostasis and ROS production are unaffected by STIM1 deficiency, but phagosomal proteolysis and leucyl aminopeptidase activity, IRAP recruitment, as well as fusion of phagosomes with endosomes and lysosomes are all impaired. These data suggest that STIM1-dependent Ca2+ signalling promotes the delivery of endolysosomal enzymes to phagosomes to enable efficient cross-presentation.
| S-EPMC5701258 | biostudies-literature
Project description:Increased antigen cross-presentation but impaired cross-priming after activation of PPARγ is mediated by up-regulation of B7H1 Dendritic cells (DCs) are able to take up exogenous antigens and present antigen-derived peptides on MHC class I molecules, a process termed cross-presentation. The mannose receptor (MR), an endocytic receptor expressed on a variety of antigen-presenting cells (APCs), has been demonstrated to target soluble antigens exclusively towards cross-presentation. In this study, we investigated the role of the murine nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated transcription factor with immunomodulatory properties, in MR-mediated endocytosis and cross-presentation of the model antigen ovalbumin (OVA). We could demonstrate both in vitro and in vivo that activation of PPARγ resulted in increased MR expression, which in consequence led to enhanced MR-mediated endocytosis and elevated cross-presentation of soluble OVA. Concomitantly, activation of PPARγ in DCs induced up-regulation of the co-inhibitory molecule B7H1, which, despite enhanced cross-presentation, caused an impaired activation of naive OVA-specific CD8+ T cells and the induction of T cell tolerance. These data provide a mechanistic basis for the immunomodulatory action of PPARγ which might open new possibilities in development of therapeutical approaches aimed at the control of excessive immune responses, e.g. in T cell-mediated autoimmunity. Comparison of murine mannose receptor negative versus mannose receptor positive bone marrow-derived DCs
2010-05-08 | E-GEOD-15616 | biostudies-arrayexpress
Project description:Mouse spleens contain three populations of conventional (CD11c(high)) dendritic cells (DCs) that play distinct functions. The CD8(+) DC are unique in that they can present exogenous antigens on their MHC class I molecules, a process known as cross-presentation. It is unclear whether this special ability is because only the CD8(+) DC can capture the antigens used in cross-presentation assays, or because this is the only DC population that possesses specialized machinery for cross-presentation. To solve this important question we examined the splenic DC subsets for their ability to both present via MHC class II molecules and cross-present via MHC class I using four different forms of the model antigen ovalbumin (OVA). These forms include a cell-associated form, a soluble form, OVA expressed in bacteria, or OVA bound to latex beads. With the exception of bacterial antigen, which was poorly cross-presented by all DC, all antigenic forms were cross-presented much more efficiently by the CD8(+) DC. This pattern could not be attributed simply to a difference in antigen capture because all DC subsets presented the antigen via MHC class II. Indeed, direct assessments of endocytosis showed that CD8(+) and CD8(-) DC captured comparable amounts of soluble and bead-associated antigen, yet only the CD8(+) DC cross-presented these antigenic forms. Our results indicate that cross-presentation requires specialized machinery that is expressed by CD8(+) DC but largely absent from CD8(-) DC. This conclusion has important implications for the design of vaccination strategies based on antigen targeting to DC.
| S-EPMC1502299 | biostudies-literature