The characterization of human dendritic cell (DC) subsets is essential for the design of new vaccines. We report the first detailed functional analysis of the human CD141+ DC subset. CD141+ DCs are found in human lymph nodes, bone marrow, tonsil, and blood, and the latter proved to be the best source of highly purified cells for functional analysis. They are characterized by high expression of toll-like receptor 3, production of IL-12p70 and IFN-β, and superior capacity to induce T helper 1 cell responses, when compared with the more commonly studied CD1c+ DC subset. Polyinosine-polycytidylic acid (poly I:C)–activated CD141+ DCs have a superior capacity to cross-present soluble protein antigen (Ag) to CD8+ cytotoxic T lymphocytes than poly I:C–activated CD1c+ DCs. Importantly, CD141+ DCs, but not CD1c+ DCs, were endowed with the capacity to cross-present viral Ag after their uptake of necrotic virus-infected cells. These findings establish the CD141+ DC subset as an important functionally distinct human DC subtype with characteristics similar to those of the mouse CD8α+ DC subset. The data demonstrate a role for CD141+ DCs in the induction of cytotoxic T lymphocyte responses and suggest that they may be the most relevant targets for vaccination against cancers, viruses, and other pathogens.

+subsets that display unique gene expression profiles, suggesting specialized functions. CD1c+ DCs express TLR4 while CD141 + DCs do not, thus predicting that these two subsets have differential capacities to respond to Escherichia coli. We isolated highly purified CD1c + and CD141 + DCs and compared them to in vitro generated monocyte-derived DCs (MoDCs) following stimulation with whole E. coli. As expected, MoDCs produced high levels of the proinflammatory cytokines TNF, IL-6, and IL-12, were potent inducers of Th1 responses, and processed E. coli-derived Ag. In contrast, CD1c + DCs produced only low levels of TNF, IL-6, and IL-12 and instead produced high levels of the anti-inflammatory cytokine IL-10 and regulatory molecules IDO and soluble CD25. Moreover, E. coli-activated CD1c + DCs suppressed T-cell proliferation in an IL-10-dependent manner. Contrary to their mouse CD8 + DC counterparts, human CD141 + DCs did not phagocytose or process E. coli-derived Ag and failed to secrete cytokines in response to E. coli. These data demonstrate substantial differences in the nature of the response of human blood DC subsets to E. coli. Keywords: E. coli r Human dendritic cells r IL-10 See accompanying Commentary by Qian and CaoSupporting Information available online IntroductionDCs are potent antigen-presenting cells that play a fundamental role in the induction and regulation of innate and adaptiveCorrespondence: Dr. Kristen J. Radford e-mail: kradford@mmri.mater.org.au immune responses against microbial pathogens. DCs detect microbial products using a sophisticated repertoire of PRR that include the toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors, retinoic acid * These authors contributed equally to this work.C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2012. 42: 1512-1522 Immunity to infection 1513 inducible gene 1 (RIG-I)-like receptors and C-type lectins. The nature of the immune response to a given pathogen is tightly regulated by the DC network, which consists of multiple subsets that are equipped with unique PRRs and are endowed with specialized functions. DCs in humans and mice can be categorized into three broad subtypes. These three subtypes are: (i) inflammatory DCs that are mobilized rapidly from monocytes in response to infection and inflammation (monocyte-derived DCs; MoDCs), (ii) migratory DCs that reside in the peripheral tissues and migrate to lymphoid tissues after encounter with Ag, and (iii) the blood and lymphoid tissue resident DCs that are comprised of plasmacytoid and myeloid DCs [1]. Further complexity arises within the steadystate myeloid DC subsets, which in humans are defined as lineage (CD3,14,15,19,20,56 ResultsMoDCs are the main DC subset responsive to E. coli CD1c + and CD141 + DCs were enriched from healthy donor leukapheresis products by immuno-magnetic selection, and flow sorted to high purity (>99%) using our established human DC isolation protocols [8,19]. Autologous MoDCs were differentiated from...

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IMPORTANCE Primary analysis of the TRAIN-2 study showed high pathologic complete response rates after neoadjuvant chemotherapy with or without anthracyclines plus dual ERBB2 (formerly HER2) blockade.OBJECTIVE To evaluate 3-year event-free survival (EFS) and overall survival (OS) of an anthracycline-free and anthracycline-containing regimen with dual ERBB2 blockade in patients with stage II and III ERBB2-positive breast cancer. DESIGN, SETTING, AND PARTICIPANTSA total of 438 patients with stage II and III ERBB2-positive breast cancer were enrolled in this randomized, clinical, open-label phase 3 trial across 37 hospitals in the Netherlands from December 9, 2013, until January 14, 2016. Follow-up analyses were performed after a median follow-up of 48.8 months (interquartile range, 44.1-55.2 months). Analysis was performed on an intention-to-treat basis.INTERVENTIONS Participants were randomly assigned on a 1:1 basis, stratified by age, tumor stage, nodal stage, and estrogen receptor status, to receive 3 cycles of fluorouracil (500 mg/m 2 ), epirubicin (90 mg/m 2 ), and cyclophosphamide (500 mg/m 2 ), followed by 6 cycles of paclitaxel and carboplatin or 9 cycles of paclitaxel (80 mg/m 2 days 1 and 8) and carboplatin (area under the concentration-time curve, 6 mg/mL/min). Both groups received trastuzumab (6 mg/kg; loading dose 8 mg/kg) and pertuzumab (420 mg intravenously; loading dose 840 mg) every 3 weeks. MAIN OUTCOMES AND MEASURES Three-year EFS, OS, and safety.RESULTS A total of 438 women were randomized, with 219 per group (anthracycline group, median age, 49 years [interquartile range, 43-55 years]; and nonanthracycline group, median age, 48 years [interquartile range, 43-56 years]). A total of 23 EFS events (10.5%) occurred in the anthracycline group and 21 EFS events (9.6%) occurred in the nonanthracycline group (hazard ratio, 0.90; 95% CI, 0.50-1.63; favoring nonanthracyclines). Three-year EFS estimates were 92.7% (95% CI, 89.3%-96.2%) in the anthracycline group and 93.6% (95% CI, 90.4%-96.9%) in the nonanthracycline group and 3-year OS estimates were 97.7% (95% CI, 95.7%-99.7%) in the anthracycline group and 98.2% (95% CI, 96.4%-100%) in the nonanthracycline group. The results were irrespective of hormone receptor and nodal status. A decline in left ventricular ejection fraction of 10% or more from baseline to less than 50% was more common in patients who received anthracyclines than those who did not (17 of 220 [7.7%] vs 7 of 218 [3.2%]; P = .04). Two patients treated with anthracyclines developed acute leukemia.CONCLUSIONS AND RELEVANCE This follow-up analysis of the TRAIN-2 study shows similar 3-year EFS and OS estimates with or without anthracyclines in patients with stage II and III ERBB2-positive breast cancer. Anthracycline use is associated with increased risk of febrile neutropenia, cardiotoxic effects, and secondary malignant neoplasms.

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