Differentiation of proinflammatory CD4+ conventional T cells (Tconv) is critical for productive antitumor responses yet their elicitation remains poorly understood. We comprehensively characterized ...myeloid cells in tumor draining lymph nodes (tdLN) of mice and identified two subsets of conventional type-2 dendritic cells (cDC2) that traffic from tumor to tdLN and present tumor-derived antigens to CD4+ Tconv, but then fail to support antitumor CD4+ Tconv differentiation. Regulatory T cell (Treg) depletion enhanced their capacity to elicit strong CD4+ Tconv responses and ensuing antitumor protection. Analogous cDC2 populations were identified in patients, and as in mice, their abundance relative to Treg predicts protective ICOS+ PD-1lo CD4+ Tconv phenotypes and survival. Further, in melanoma patients with low Treg abundance, intratumoral cDC2 density alone correlates with abundant CD4+ Tconv and with responsiveness to anti-PD-1 therapy. Together, this highlights a pathway that restrains cDC2 and whose reversal enhances CD4+ Tconv abundance and controls tumor growth.
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•cDC2 initiate activation but not differentiation of antitumor CD4+ Tconv•Treg depletion relieves cDC2 suppression driving antitumor CD4+ Tconv differentiation•Human equivalent of mouse cDC2 are present in the tumor and draining lymph node•The balance of human cDC2/Treg in the TME dictates T cell quality and prognosis
A subtype of conventional dendritic cells, cDC2, are able to prime CD4+ T cells for antitumor functions and the presence of cDC2 in human cancer samples may serve as a predictive biomarker for survival and response to immune checkpoint blockade.
Conventional type 1 dendritic cells (cDC1)
are thought to perform antigen cross-presentation, which is required to prime CD8
T cells
, whereas cDC2 are specialized for priming CD4
T cells
. CD4
T ...cells are also considered to help CD8
T cell responses through a variety of mechanisms
, including a process whereby CD4
T cells 'license' cDC1 for CD8
T cell priming
. However, this model has not been directly tested in vivo or in the setting of help-dependent tumour rejection. Here we generated an Xcr1
mouse strain to evaluate the cellular interactions that mediate tumour rejection in a model requiring CD4
and CD8
T cells. As expected, tumour rejection required cDC1 and CD8
T cell priming required the expression of major histocompatibility class I molecules by cDC1. Unexpectedly, early priming of CD4
T cells against tumour-derived antigens also required cDC1, and this was not simply because they transport antigens to lymph nodes for processing by cDC2, as selective deletion of major histocompatibility class II molecules in cDC1 also prevented early CD4
T cell priming. Furthermore, deletion of either major histocompatibility class II or CD40 in cDC1 impaired tumour rejection, consistent with a role for cognate CD4
T cell interactions and CD40 signalling in cDC1 licensing. Finally, CD40 signalling in cDC1 was critical not only for CD8
T cell priming, but also for initial CD4
T cell activation. Thus, in the setting of tumour-derived antigens, cDC1 function as an autonomous platform capable of antigen processing and priming for both CD4
and CD8
T cells and of the direct orchestration of their cross-talk that is required for optimal anti-tumour immunity.
Plasmacytoid dendritic cells (pDCs) are a unique DC subset that specializes in the production of type I interferons (IFNs). pDCs promote antiviral immune responses and have been implicated in the ...pathogenesis of autoimmune diseases that are characterized by a type I IFN signature. However, pDCs can also induce tolerogenic immune responses. In this Review, we summarize recent progress in the field of pDC biology, focusing on the molecular mechanisms that regulate the development and functions of pDCs, the pathways involved in their sensing of pathogens and endogenous nucleic acids, their functions at mucosal sites, and their roles in infection, autoimmunity and cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Given the limited efficacy of clinical approaches that rely on ex vivo generated dendritic cells (DCs), it is imperative to design strategies that harness specialized DC subsets in situ. This ...requires delineating the expression of surface markers by DC subsets among individuals and tissues. Here, we performed a multiparametric phenotypic characterization and unbiased analysis of human DC subsets in blood, tonsil, spleen, and skin. We uncovered previously unreported phenotypic heterogeneity of human cDC2s among individuals, including variable expression of functional receptors such as CD172a. We found marked differences in DC subsets localized in blood and lymphoid tissues versus skin, and a striking absence of the newly discovered Axl+ DCs in the skin. Finally, we evaluated the capacity of anti-receptor monoclonal antibodies to deliver vaccine components to skin DC subsets. These results offer a promising path for developing DC subset-specific immunotherapies that cannot be provided by transcriptomic analysis alone.
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•CyTOF reveals interindividual heterogeneity among DC subsets, especially cDC2s•Human skin harbors cDCs with a unique phenotype and lacks Axl+ DCs•Axl+ DCs display phenotypic and functional diversity, and pDCs exhibit plasticity•Receptor profiling identifies targets for antigen delivery to skin DC subsets
Dendritic cells (DCs) are potent initiators of immune responses; however, human DC subsets have yet to be successfully harnessed for immunotherapies. By combining CyTOF and unbiased analysis, Alcántara-Hernández et al. profile the heterogeneity of human DC subsets among individuals and tissues, providing comprehensive insights for the development of DC-based therapeutics.
Regulation of tryptophan metabolism by indoleamine 2,3-dioxygenase (IDO) in dendritic cells (DCs) is a highly versatile modulator of immunity. In inflammation, interferon-γ is the main inducer of IDO ...for the prevention of hyperinflammatory responses, yet IDO is also responsible for self-tolerance effects in the longer term. Here we show that treatment of mouse plasmacytoid DCs (pDCs) with transforming growth factor-β (TGF-β) conferred regulatory effects on IDO that were mechanistically separable from its enzymic activity. We found that IDO was involved in intracellular signaling events responsible for the self-amplification and maintenance of a stably regulatory phenotype in pDCs. Thus, IDO has a tonic, nonenzymic function that contributes to TGF-β-driven tolerance in noninflammatory contexts.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dendritic cells (DCs) are a heterogeneous group of functionally specialized antigen-presenting cells that initiate and orchestrate immune responses. Our understanding of DC immunobiology has been ...largely shaped by research using murine models. The relevance of murine findings on human DC organization and function is only just beginning to be investigated. In this chapter, we present the key historical developments and recent advances in human and mouse DC research to contextualize the existing knowledge on DC subset origin and functional specializations. We also propose a framework to align human and mouse DC networks to enhance our understanding of the parallel organization of DCs in both species in order to facilitate the full exploitation of our knowledge on DC biology and function for clinical therapeutic strategies.
The intestinal immune system is continuously exposed to massive amounts of nanoparticles derived from food. Whether nanoparticles from plants we eat daily have a role in maintaining intestinal immune ...homeostasis is poorly defined. Here, we present evidence supporting our hypothesis that edible nanoparticles regulate intestinal immune homeostasis by targeting dendritic cells (DCs). Using three mouse colitis models, our data show that orally given nanoparticles isolated from broccoli extracts protect mice against colitis. Broccoli-derived nanoparticle (BDN)-mediated activation of adenosine monophosphate-activated protein kinase (AMPK) in DCs plays a role in not only prevention of DC activation but also induction of tolerant DCs. Adoptively transferring DCs pre-pulsed with total BDN lipids, but not sulforaphane (SFN)-depleted BDN lipids, prevented DSS-induced colitis in C57BL/6 (B6) mice, supporting the role of BDN SFN in the induction of DC tolerance. Adoptively transferring AMPK+/+, but not AMPK−/−, DCs pre-pulsed with SFN prevented DSS-induced colitis in B6 mice, further supporting the DC AMPK role in SFN-mediated prevention of DSS-induced colitis. This finding could open new preventive or therapeutic avenues to address intestinal-related inflammatory diseases via activating AMPK.
The intestinal immune system is continuously exposed to massive amounts of nanoparticles derived from food. As proof of concept, in this issue of Molecular Therapy, Deng et al. show that nanoparticles isolated from broccoli extracts protected mice from developing colitis by induction of tolerant dendritic cells through the adenosine monophosphate-activated protein kinase-mediated pathway.
Dendritic cells as gatekeepers of tolerance Waisman, Ari; Lukas, Dominika; Clausen, Björn E. ...
Seminars in Immunopathology,
02/2017, Letnik:
39, Številka:
2
Journal Article, Book Review
Recenzirano
Dendritic cells (DC) are unique hematopoietic cells, linking innate and adaptive immune responses. In particular, they are considered as the most potent antigen presenting cells, governing both T ...cell immunity and tolerance. In view of their exceptional ability to present antigen and to interact with T cells, DC play distinct roles in shaping T cell development, differentiation and function. The outcome of the DC-T cell interaction is determined by the state of DC maturation, the type of DC subset, the cytokine microenvironment and the tissue location. Both regulatory T cells (Tregs) and DC are indispensable for maintaining central and peripheral tolerance. Over the past decade, accumulating data indicate that DC critically contribute to Treg differentiation and homeostasis.
Anti-PD-1 immune checkpoint blockers can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Here, we combined intravital real-time imaging ...with single-cell RNA sequencing analysis and mouse models to uncover anti-PD-1 pharmacodynamics directly within tumors. We showed that effective antitumor responses required a subset of tumor-infiltrating dendritic cells (DCs), which produced interleukin 12 (IL-12). These DCs did not bind anti-PD-1 but produced IL-12 upon sensing interferon γ (IFN-γ) that was released from neighboring T cells. In turn, DC-derived IL-12 stimulated antitumor T cell immunity. These findings suggest that full-fledged activation of antitumor T cells by anti-PD-1 is not direct, but rather involves T cell:DC crosstalk and is licensed by IFN-γ and IL-12. Furthermore, we found that activating the non-canonical NF-κB transcription factor pathway amplified IL-12-producing DCs and sensitized tumors to anti-PD-1 treatment, suggesting a therapeutic strategy to improve responses to checkpoint blockade.
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•Effective anti-PD-1 anti-tumor responses require IL-12-producing dendritic cells•Anti-PD-1 indirectly activates IL-12 through IFN-γ produced from CD8+ T cells•Agonizing the non-canonical NF-κB pathway enhances dendritic cell IL-12 production•Combining aPD-1 with non-canonical NF-κB agonism enhances checkpoint immunotherapy
Anti-PD-1 mAbs can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Garris et al. show that effective anti-PD-1 immunotherapy requires intratumoral dendritic cells (DCs) producing IL-12. Anti-PD-1 indirectly activates DCs through IFN-γ released from drug-activated T cells. Furthermore, agonizing the non-canonical NF-κB pathway activates DCs and enhances aPD-1 therapy in an IL-12-dependent manner.
The role of different DC subsets in priming and maintenance of immunity against Leishmania major (L. major) infection is debated. The transcription factor basic leucine zipper transcription factor, ...ATF‐like 3 (Batf3) is essential for the development of mouse CD103+ DCs and some functions of CD8α+ DCs. We found that CD103+ DCs were significantly reduced in the dermis of Batf3‐deficient C57BL/6 mice. Batf3−/− mice developed exacerbated and unresolved cutaneous pathology following a low dose of intradermal L. major infection in the ear pinnae. Parasite load was increased 1000‐fold locally and expanded systemically. Batf3 deficiency did not affect L. major antigen presentation to T cells, which was directly exerted by CD8α− conventional DCs (cDCs) in the skin draining LN. However, CD4+ T‐cell differentiation in the LN and skin was skewed to nonprotective Treg‐ and Th2‐cell subtypes. CD103+ DCs are major IL‐12 producers during L. major infection. Local Th1 immunity was severely hindered, correlating with impaired IL‐12 production and reduction in CD103+ DC numbers. Adoptive transfer of WT but not IL‐12p40−/− Batf3‐dependent DCs significantly improved anti‐L. major response in infected Batf3−/− mice. Our results suggest that IL‐12 production by Batf3‐dependent CD103+ DCs is crucial for maintenance of local Th1 immunity against L. major infection.
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