Human CD1c+ dendritic cells secrete high levels of IL-12 and potently prime cytotoxic T-cell responses

Nizzoli, Giulia; Krietsch, Jana; Weick, Anja; Steinfelder, Svenja; Facciotti, Federica; Gruarin, Paola; Bianco, Annalisa; Steckel, Bodo; Moro, Monica; Crosti, Mariacristina; Romagnani, Chiara; Stölzel, Katharina; Torretta, Sara; Pignataro, Lorenzo; Scheibenbogen, Carmen; Neddermann, Petra; Francesco, Raffaele De; Abrignani, Sergio; Geginat, Jens

doi:10.1182/blood-2013-04-495424

Cited by 280 publications

(272 citation statements)

References 53 publications

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“…Less than 2% of live cells (mean 6 SD, 1.5 6 0.6%) were expressing CD1c whereas .90% of live monocytes harbored high CD14 expression levels (mean 6 SD, 92.2 6 3.2%), suggesting that langerin high MDLCs arose from classical monocytes and not from CD1c + contaminant cells endowed with a low proliferative potential (Supplemental Fig. 1C) (39). To compare classical monocytes with CD1c + blood DCs, which were recently shown to exhibit a high differentiation potential toward LC-like cells (31,32), both cell types were sorted from blood of healthy donors and differentiated with GM-CSF and TGF-b1 in 2% HSA for 7 d. A flow cytometric analysis of their respective CD1a and langerin expression showed similar abilities to differentiate into langerin high CD1a high cells (R3 gate; Fig.…”

Section: Resultsmentioning

confidence: 99%

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

Picarda

Chéneau

Humbert

et al. 2016

The Journal of Immunology

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Langerhans cells (LCs) are epithelial APCs that sense danger signals and in turn trigger specific immune responses. In steady-state, they participate in the maintenance of peripheral tolerance to self-antigens whereas under inflammation LCs efficiently trigger immune responses in secondary lymphoid organs. It has been demonstrated in mice that LC-deprived epithelia are rapidly replenished by short half-life langerin-expressing monocyte-derived LCs (MDLCs). These surrogate LCs are thought to be progressively replaced by langerinhigh LCs arising from self-renewing epithelial precursors of hematopoietic origin. How LCs arise from blood monocytes is not fully understood. Hence, we sought to characterize key factors that induce differentiation of langerinhigh-expressing monocyte-derived Langerhans-like cells. We identified GM-CSF and TGF-β1 as key cytokines to generate langerinhigh-expressing cells but only in serum-free conditions. These cells were shown to express the LC-specific TROP-2 and Axl surface markers and contained Birbeck granules. Surprisingly, E-cadherin was not spontaneously expressed by these cells but required a direct contact with keratinocytes to be stably induced. MDLCs induced stronger allogeneic T cell proliferations but released low amounts of inflammatory cytokines upon TLR stimulation compared with donor-paired monocyte-derived dendritic cells. Immature langerinhigh MDLCs were responsive to MIP-3β/CCL20 and CTAC/CCL27 chemokine stimulations. Finally, we demonstrated that those cells behaved as bona fide LCs when inserted in a three-dimensional rebuilt epithelium by becoming activated upon TLR or UV light stimulations. Collectively, these results prompt us to propose these langerinhigh MDLCs as a relevant model to address LC biology–related questions.

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Section: Resultsmentioning

confidence: 99%

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

Picarda

Chéneau

Humbert

et al. 2016

The Journal of Immunology

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“…Although the trial was designed as a safety and feasibility study, we obtained promising clinical results; 7 of 15 metastatic melanoma patients were still alive two years after the initiation of treatment (14). Both activated pDCs, which produce high amounts of IFNa, and activated mDCs have the capacity to induce T helper 1 cells, cytotoxic T cells, natural killer cells, and natural killer T cells, leading to a potent cellular immune response (15)(16)(17). Moreover, primary mDCs isolated from healthy donors and cancer patients are able to prime tumor-specific CD8 þ T cells in vitro (18).…”

Section: Introductionmentioning

confidence: 99%

Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells

Schreibelt

Bol

Westdorp

et al. 2016

Clinical Cancer Research

198

177

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Purpose: Thus far, dendritic cell (DC)-based immunotherapy of cancer was primarily based on in vitro-generated monocytederived DCs, which require extensive in vitro manipulation. Here, we report on a clinical study exploiting primary CD1c þ myeloid DCs, naturally circulating in the blood. Experimental Design: Fourteen stage IV melanoma patients, without previous systemic treatment for metastatic disease, received autologous CD1c þ myeloid DCs, activated by only brief (16 hours) ex vivo culture and loaded with tumor-associated antigens of tyrosinase and gp100. Results: Our results show that therapeutic vaccination against melanoma with small amounts (3-10 Â 10 6 ) of myeloid DCs is feasible and without substantial toxicity. Four of 14 patients showed long-term progression-free survival (12-35 months), which directly correlated with the development of multifunctional CD8þ T-cell responses in three of these patients. In particular, high CD107a expression, indicative for cytolytic activity, and IFNg as well as TNFa and CCL4 production was observed. Apparently, these T-cell responses are essential to induce tumor regression and promote long-term survival by stalling tumor growth. Conclusions:We show that vaccination of metastatic melanoma patients with primary myeloid DCs is feasible and safe and results in induction of effective antitumor immune responses that coincide with improved progression-free survival. Clin Cancer Res; 22(9); 2155-66. Ó2015 AACR.

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“…It depends on the tissue origin of the DC subsets, on their activation status, and on the mode of Ag delivery (7)(8)(9)(10)(18)(19)(20)(21)(22)(23). However, several independent studies showed that human XCR1 + blood DC (bDC) excel at cross-presentation of cell-associated Ags (8)(9)(10)18) and of particulate Ags delivered through FcgRs, through lysosomes (19,20) or upon polyI:C stimulation (8,10,23). Because they share unique characteristics with mouse XCR1 + DC, human XCR1 + bDC constitute a distinct human DC subset that may have potential clinical applications (24)(25)(26).…”

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confidence: 99%

Human XCR1+ Dendritic Cells Derived In Vitro from CD34+ Progenitors Closely Resemble Blood Dendritic Cells, Including Their Adjuvant Responsiveness, Contrary to Monocyte-Derived Dendritic Cells

Balan

Ollion

Colletti

et al. 2014

The Journal of Immunology

112

154

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Human monocyte-derived dendritic cell (MoDC) have been used in the clinic with moderately encouraging results. Mouse XCR1+ DC excel at cross-presentation, can be targeted in vivo to induce protective immunity, and share characteristics with XCR1+ human DC. Assessment of the immunoactivation potential of XCR1+ human DC is hindered by their paucity in vivo and by their lack of a well-defined in vitro counterpart. We report in this study a protocol generating both XCR1+ and XCR1− human DC in CD34+ progenitor cultures (CD34-DC). Gene expression profiling, phenotypic characterization, and functional studies demonstrated that XCR1− CD34-DC are similar to canonical MoDC, whereas XCR1+ CD34-DC resemble XCR1+ blood DC (bDC). XCR1+ DC were strongly activated by polyinosinic-polycytidylic acid but not LPS, and conversely for MoDC. XCR1+ DC and MoDC expressed strikingly different patterns of molecules involved in inflammation and in cross-talk with NK or T cells. XCR1+ CD34-DC but not MoDC efficiently cross-presented a cell-associated Ag upon stimulation by polyinosinic-polycytidylic acid or R848, likewise to what was reported for XCR1+ bDC. Hence, it is feasible to generate high numbers of bona fide XCR1+ human DC in vitro as a model to decipher the functions of XCR1+ bDC and as a potential source of XCR1+ DC for clinical use.

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Human CD1c+ dendritic cells secrete high levels of IL-12 and potently prime cytotoxic T-cell responses

Abstract: Key Points CD1c+ DC but not BDCA-3+ DC or other antigen-presenting cells secrete high amounts of bioactive IL-12. CD1c+ DC efficiently cross-present antigens, prime CD8+ T cells, and induce the highest levels of cytotoxic molecules.

Cited by 280 publications

References 53 publications

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells

Human XCR1+ Dendritic Cells Derived In Vitro from CD34+ Progenitors Closely Resemble Blood Dendritic Cells, Including Their Adjuvant Responsiveness, Contrary to Monocyte-Derived Dendritic Cells

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