Dopamine-induced pruning in monocyte-derived-neuronal-like cells (MDNCs) from patients with schizophrenia.

The long lapse between the presumptive origin of schizophrenia (SCZ) during early development and its diagnosis in late adolescence has hindered the study of crucial neurodevelopmental processes directly in living patients. Dopamine, a neurotransmitter consistently associated with the pathophysiology of SCZ, participates in several aspects of brain development including pruning of neuronal extensions. Excessive pruning is considered the cause of the most consistent finding in SCZ, namely decreased brain volume. It is therefore possible that patients with SCZ carry an increased susceptibility to dopamine's pruning effects and that this susceptibility would be more obvious in the early stages of neuronal development when dopamine pruning effects appear to be more prominent. Obtaining developing neurons from living patients is not feasible. Instead, we used Monocyte-Derived-Neuronal-like Cells (MDNCs) as these cells can be generated in only 20 days and deliver reproducible results. In this study, we expanded the number of individuals in whom we tested the reproducibility of MDNCs. We also deepened the characterization of MDNCs by comparing its neurostructure to that of human developing neurons. Moreover, we studied MDNCs from 12 controls and 13 patients with SCZ. Patients' cells differentiate more efficiently, extend longer secondary neurites and grow more primary neurites. In addition, MDNCs from medicated patients expresses less D1R and prune more primary neurites when exposed to dopamine. Haloperidol did not influence our results but the role of other antipsychotics was not examined and thus, needs to be considered as a confounder.

A tribute to Nilabh Shastri and a special issue on antigen processing and presentation in Paris (APP10, Paris 2019).

The Special Issue is dedicated to the 10th Antigen Processing and Presentation Workshop, which took place at Institut Cochin in Paris from May 28th to June 2nd, 2019. It contains several reviews or original articles from contributors to this workshop. It is also a vibrant Tribute to Nilabh Shastri, founder of the APP Workshops, who untimely passed away in 2021 and is deeply missed by his colleagues and friends.

Cell-Associated HIV Cross-Presentation by Plasmacytoid Dendritic Cells Is Potentiated by Noncognate CD8+ T Cell Preactivation.

IFN-γ secretion by Ag-specific T cells is known to be tightly regulated by engagement of the TCR. Human plasmacytoid dendritic cells (pDC) can cross-present Ags from apoptotic HIV-infected cells or tumor cells to CD8+ T cells. As pDC respond to HIV virions by maturing and secreting cytokines, we hypothesized that this might affect cross-presentation from HIV-infected cells. Purified blood DC were incubated with apoptotic HIV-infected H9 cells in the presence of saquinavir, after which the activation process of HIV-specific cloned CD8+ T cells was studied. IFN-γ secretion by HIV-specific T cells was stimulated by pDC and conventional DC (cDC1) more than by cDC2 and was strictly MHC class I restricted. Surprisingly, intracellular production of IFN-γ was only partly MHC class I restricted for pDC, indicating a noncognate CD8+ T cell activation. pDC, but not cDC, matured and secreted IFN-α in the presence of apoptotic H9HIV cells. A mixture of IFN-α, IFN-ß, and TNF-α induced intracellular production of IFN-γ but not granzyme B, mimicking the noncognate mechanism. Neutralization of type I IFN signaling blocked noncognate intracellular production of IFN-γ. Moreover, cognate stimulation was required to induce IFN-γ secretion in addition to the cytokine mixture. Thus, IFN-γ secretion is tightly regulated by engagement of the TCR as expected, but in the context of virus-infected cells, pDC can trigger intracellular IFN-γ accumulation in CD8+ T cells, potentializing IFN-γ secretion once CD8+ T cells make cognate interactions. These findings may help manipulate type I IFN signaling to enhance specifically Ag-specific CD8+ T cell activation against chronic infections or tumors.

Conventional Dendritic Cells and Slan+ Monocytes During HIV-2 Infection.

HIV-2 infection is characterized by low viremia and slow disease progression as compared to HIV-1 infection. Circulating CD14++CD16+ monocytes were found to accumulate and CD11c+ conventional dendritic cells (cDC) to be depleted in a Portuguese cohort of people living with HIV-2 (PLWHIV-2), compared to blood bank healthy donors (HD). We studied more precisely classical monocytes; CD16+ inflammatory (intermediate, non-classical and slan+ monocytes, known to accumulate during viremic HIV-1 infection); cDC1, important for cross-presentation, and cDC2, both depleted during HIV-1 infection. We analyzed by flow cytometry these PBMC subsets from Paris area residents: 29 asymptomatic, untreated PLWHIV-2 from the IMMUNOVIR-2 study, part of the ANRS-CO5 HIV-2 cohort: 19 long-term non-progressors (LTNP; infection ≥8 years, undetectable viral load, stable CD4 counts≥500/µL; 17 of West-African origin -WA), and 10 non-LTNP (P; progressive infection; 9 WA); and 30 age-and sex-matched controls: 16 blood bank HD with unknown geographical origin, and 10 HD of WA origin (GeoHD). We measured plasma bacterial translocation markers by ELISA. Non-classical monocyte counts were higher in GeoHD than in HD (54 vs. 32 cells/µL, p = 0.0002). Slan+ monocyte counts were twice as high in GeoHD than in HD (WA: 28 vs. 13 cells/µL, p = 0.0002). Thus cell counts were compared only between participants of WA origin. They were similar in LTNP, P and GeoHD, indicating that there were no HIV-2 related differences. cDC counts did not show major differences between the groups. Interestingly, inflammatory monocyte counts correlated with plasma sCD14 and LBP only in PLWHIV-2, especially LTNP, and not in GeoHD. In conclusion, in LTNP PLWHIV-2, inflammatory monocyte counts correlated with LBP or sCD14 plasma levels, indicating a potential innate immune response to subclinical bacterial translocation. As GeoHD had higher inflammatory monocyte counts than HD, our data also show that specific controls are important to refine innate immunity studies.

Monitoring antigen cross-presentation by human dendritic cells purified from peripheral blood.

Tumor immunosurveillance, regression and therapy require most often the action of CD8+ T cells. These cells are primed by dendritic cells (DC), which are the only antigen presenting cells able to stimulate naive T cells. Tumor antigen presentation requires cross-presentation of antigens from the tumor cells by DC. Dendritic cells capture antigens from tumor cells into endosomal compartments and process them. Then they expose at their cell surface their own MHC class I molecules complexed with tumor cell epitopes, which are recognized by the T cell receptors of specific CD8+ T cells. This allows the activation of anti-tumoral functions of these specific CD8+ T cells, mediated by cytokines and by cytotoxic mechanisms. Here, we describe in detail the delicate methods required to (1) prepare antigen donor cells, (2) prepare CD8+ T cells specific for these antigens, (3) purify human DC from peripheral blood, (4) preincubate purified DC and antigen donor cells for antigen capture, (5) incubate these DC with antigen-specific CD8+ T cells for cross-presentation and (6) assess cross-presentation to specific CD8+ T cells. These methods allowed our laboratory to characterize in detail cross-presentation from cells containing viral antigens and can be applied to study cross-presentation from tumor antigens.

Limited HIV-2 reservoirs in central-memory CD4 T-cells associated to CXCR6 co-receptor expression in attenuated HIV-2 infection.

The low pathogenicity and replicative potential of HIV-2 are still poorly understood. We investigated whether HIV-2 reservoirs might follow the peculiar distribution reported in models of attenuated HIV-1/SIV infections, i.e. limited infection of central-memory CD4 T lymphocytes (TCM). Antiretroviral-naive HIV-2 infected individuals from the ANRS-CO5 (12 non-progressors, 2 progressors) were prospectively included. Peripheral blood mononuclear cells (PBMCs) were sorted into monocytes and resting CD4 T-cell subsets (naive [TN], central- [TCM], transitional- [TTM] and effector-memory [TEM]). Reactivation of HIV-2 was tested in 30-day cultures of CD8-depleted PBMCs. HIV-2 DNA was quantified by real-time PCR. Cell surface markers, co-receptors and restriction factors were analyzed by flow-cytometry and multiplex transcriptomic study. HIV-2 DNA was undetectable in monocytes from all individuals and was quantifiable in TTM from 4 individuals (median: 2.25 log10 copies/106 cells [IQR: 1.99-2.94]) but in TCM from only 1 individual (1.75 log10 copies/106 cells). HIV-2 DNA levels in PBMCs (median: 1.94 log10 copies/106 PBMC [IQR = 1.53-2.13]) positively correlated with those in TTM (r = 0.66, p = 0.01) but not TCM. HIV-2 reactivation was observed in the cells from only 3 individuals. The CCR5 co-receptor was distributed similarly in cell populations from individuals and donors. TCM had a lower expression of CXCR6 transcripts (p = 0.002) than TTM confirmed by FACS analysis, and a higher expression of TRIM5 transcripts (p = 0.004). Thus the low HIV-2 reservoirs differ from HIV-1 reservoirs by the lack of monocytic infection and a limited infection of TCM associated to a lower expression of a potential alternative HIV-2 co-receptor, CXCR6 and a higher expression of a restriction factor, TRIM5. These findings shed new light on the low pathogenicity of HIV-2 infection suggesting mechanisms close to those reported in other models of attenuated HIV/SIV infection models.

HIV-1 reservoirs in urethral macrophages of patients under suppressive antiretroviral therapy.

Human immunodeficiency virus type 1 (HIV-1) eradication is prevented by the establishment on infection of cellular HIV-1 reservoirs that are not fully characterized, especially in genital mucosal tissues (the main HIV-1 entry portal on sexual transmission). Here, we show, using penile tissues from HIV-1-infected individuals under suppressive combination antiretroviral therapy, that urethral macrophages contain integrated HIV-1 DNA, RNA, proteins and intact virions in virus-containing compartment-like structures, whereas viral components remain undetectable in urethral T cells. Moreover, urethral cells specifically release replication-competent infectious HIV-1 following reactivation with the macrophage activator lipopolysaccharide, while the T-cell activator phytohaemagglutinin is ineffective. HIV-1 urethral reservoirs localize preferentially in a subset of polarized macrophages that highly expresses the interleukin-1 receptor, CD206 and interleukin-4 receptor, but not CD163. To our knowledge, these results are the first evidence that human urethral tissue macrophages constitute a principal HIV-1 reservoir. Such findings are determinant for therapeutic strategies aimed at HIV-1 eradication.

Transdifferentiation of Human Circulating Monocytes Into Neuronal-Like Cells in 20 Days and Without Reprograming.

Despite progress, our understanding of psychiatric and neurological illnesses remains poor, at least in part due to the inability to access neurons directly from patients. Currently, there are in vitro models available but significant work remains, including the search for a less invasive, inexpensive and rapid method to obtain neuronal-like cells with the capacity to deliver reproducible results. Here, we present a new protocol to transdifferentiate human circulating monocytes into neuronal-like cells in 20 days and without the need for viral insertion or reprograming. We have thoroughly characterized these monocyte-derived-neuronal-like cells (MDNCs) through various approaches including immunofluorescence (IF), flow cytometry, qRT-PCR, single cell mRNA sequencing, electrophysiology and pharmacological techniques. These MDNCs resembled human neurons early in development, expressed a variety of neuroprogenitor and neuronal genes as well as several neuroprogenitor and neuronal proteins and also presented electrical activity. In addition, when these neuronal-like cells were exposed to either dopamine or colchicine, they responded similarly to neurons by retracting their neuronal arborizations. More importantly, MDNCs exhibited reproducible differentiation rates, arborizations and expression of dopamine 1 receptors (DR1) on separate sequential samples from the same individual. Differentiation efficiency measured by cell morphology was on average 11.9 ± 1.4% (mean, SEM, n = 38,819 cells from 15 donors). To provide context and help researchers decide which in vitro model of neuronal development is best suited to address their scientific question,we compared our results with those of other in vitro models currently available and exposed advantages and disadvantages of each paradigm.

Chronic Type I IFN Is Sufficient To Promote Immunosuppression through Accumulation of Myeloid-Derived Suppressor Cells.

Failure of the immune system to eradicate viruses results in chronic viral infections, which are associated with increased susceptibility to secondary infections. Pathogenic HIV or lymphocytic choriomeningitis virus chronic infections display a persistent type I IFN signature. In chronic lymphocytic choriomeningitis virus infection, blockade of type I IFN signaling partially restores antiviral responses. In a mouse model, we tested whether chronic administration of type I IFN, at doses mimicking chronic viral infection, induced immunosuppression. Chronic exposure of mice to IFN-α alone was sufficient to strongly suppress specific CD8+ T cells responses to subsequent vaccinia virus infection. It resulted in the accumulation of Ly6Chi monocytes. These monocytes were similar, phenotypically and functionally, to the myeloid-derived suppressor cells found in cancer because they exerted a potent suppression on CD8+ T cell responses in vitro. They acted at least partly through the l-arginine pathway. In vivo, their elimination restored antiviral CD8+ T cell responses. Our work provides a specific mechanism accounting for the role of IFN-α in immunosuppression and predicts that type I IFN modulation will be pivotal to cure human chronic infections, cancer, or autoimmune diseases.

Plasmacytoid dendritic cells and myeloid cells differently contribute to B-cell-activating factor belonging to the tumor necrosis factor superfamily overexpression during primary HIV infection.

BACKGROUND: After describing heightened levels of circulating B-cell-activating factor belonging to the tumor necrosis factor superfamily (BAFF) as well as changes in B-cell phenotype and functions during acute infection by simian immunodeficiency virus, we wanted to determine whether and by which cells BAFF was over-expressed in primary HIV-infected (PHI) patients. DESIGN AND METHODS: We simultaneously examined circulating BAFF levels by ELISA and membrane-bound BAFF (mBAFF) expression by flow cytometry in peripheral blood mononuclear cells of healthy donors and PHI patients followed for 6 months. We also examined whether HIV-1 modifies BAFF expression or release in various myeloid cells and plasmacytoid dendritic cells (pDC) in vitro. RESULTS: Circulating BAFF levels were transiently increased at enrolment. They positively correlated with CXCL10 levels and inversely with B-cell counts. Whereas mBAFF was expressed by most pDC and on a fraction of intermediate monocytes in healthy donors, the frequency of mBAFF cells significantly increased among nonclassical monocytes and CD1c dendritic cells but decreased among pDC in PHI patients. In contrast to myeloid cells, pDC never released BAFF upon stimulation. Their mBAFF expression was enhanced by HIV-1, independently of type I IFN. CONCLUSION: Our findings reveal that the pattern of BAFF expression by myeloid cells and pDC is altered in PHI patients and constitutes a valuable marker of immune activation whose circulating levels correlate with CXCL10 levels. Due to their homing in different tissue areas, pDC and myeloid cells might target different B-cell subsets through their mBAFF expression or soluble BAFF release.

HIV-Infected Spleens Present Altered Follicular Helper T Cell (Tfh) Subsets and Skewed B Cell Maturation.

Follicular helper T (Tfh) cells within secondary lymphoid organs control multiple steps of B cell maturation and antibody (Ab) production. HIV-1 infection is associated with an altered B cell differentiation and Tfh isolated from lymph nodes of HIV-infected (HIV+) individuals provide inadequate B cell help in vitro. However, the mechanisms underlying this impairment of Tfh function are not fully defined. Using a unique collection of splenocytes, we compared the frequency, phenotype and transcriptome of Tfh subsets in spleens from HIV negative (HIV-) and HIV+ subjects. We observed an increase of CXCR5+PD-1highCD57-Tfh and germinal center (GC) CD57+ Tfh in HIV+ spleens. Both subsets showed a reduced mRNA expression of the transcription factor STAT-3, co-stimulatory, regulatory and signal transduction molecules as compared to HIV- spleens. Similarly, Foxp3 expressing follicular regulatory T (Tfr) cells were increased, suggesting sustained GC reactions in chronically HIV+ spleens. As a consequence, GC B cell populations were expanded, however, complete maturation into memory B cells was reduced in HIV+ spleens where we evidenced a compromised production of B cell-activating cytokines such as IL-4 and IL-10. Collectively our data indicate that, although Tfh proliferation and GC reactions seem to be ongoing in HIV-infected spleens, Tfh "differentiation" and expression of costimulatory molecules is skewed with a profound effect on B cell maturation.

Investigating Evolutionary Conservation of Dendritic Cell Subset Identity and Functions.

Dendritic cells (DCs) were initially defined as mononuclear phagocytes with a dendritic morphology and an exquisite efficiency for naïve T-cell activation. DC encompass several subsets initially identified by their expression of specific cell surface molecules and later shown to excel in distinct functions and to develop under the instruction of different transcription factors or cytokines. Very few cell surface molecules are expressed in a specific manner on any immune cell type. Hence, to identify cell types, the sole use of a small number of cell surface markers in classical flow cytometry can be deceiving. Moreover, the markers currently used to define mononuclear phagocyte subsets vary depending on the tissue and animal species studied and even between laboratories. This has led to confusion in the definition of DC subset identity and in their attribution of specific functions. There is a strong need to identify a rigorous and consensus way to define mononuclear phagocyte subsets, with precise guidelines potentially applicable throughout tissues and species. We will discuss the advantages, drawbacks, and complementarities of different methodologies: cell surface phenotyping, ontogeny, functional characterization, and molecular profiling. We will advocate that gene expression profiling is a very rigorous, largely unbiased and accessible method to define the identity of mononuclear phagocyte subsets, which strengthens and refines surface phenotyping. It is uniquely powerful to yield new, experimentally testable, hypotheses on the ontogeny or functions of mononuclear phagocyte subsets, their molecular regulation, and their evolutionary conservation. We propose defining cell populations based on a combination of cell surface phenotyping, expression analysis of hallmark genes, and robust functional assays, in order to reach a consensus and integrate faster the huge but scattered knowledge accumulated by different laboratories on different cell types, organs, and species.

Classification of current anticancer immunotherapies.

During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.

Altered antigen-presenting cells during HIV-1 infection.

PURPOSE OF REVIEW: The purpose of this study is to describe the alterations that HIV-1 induces in antigen-presenting cells (APCs), in vitro, ex vivo and in vivo. RECENT FINDINGS: HIV-1 disarms several arms of the immune system including APCs. We summarize here recent findings on the impact of the virus on APC. SUMMARY: HIV-1 can invade APC and overall reduce their capacity to present antigens effectively, mostly by reducing their numbers and inducing permanent hyperactivation. This occurs via a combination of alterations; however, the host can counteract, at least in part, some of these defects via restriction factors, autophagy, the production of type I interferon, antiviral cytokines, among others. However, these specific mechanisms of viral evasion from APCs' control lead to a chronic hyperactivation of the immune system implicated in AIDS-related and non-AIDS related pathogenesis. Unfortunately, the current regimens of antiretroviral therapy are unable to dampen sufficiently APC-driven viral-induced immune hyperactivation. Understanding how HIV alters APC will help to tune appropriately both intrinsic immunity and innate immunity, as well as achieve efficient antigen presentation to the adaptive immune system, without inducing a detrimental pervasive hyperactivation of the immune system.

Apoptotic cell capture by DCs induces unexpectedly robust autologous CD4+ T-cell responses.

Apoptotic cells represent an important source of self-antigens and their engulfment by dendritic cells (DCs) is usually considered to be related to tolerance induction. We report here an unexpectedly high level of human CD4(+) T-cell proliferation induced by autologous DCs loaded with autologous apoptotic cells, due to the activation of more than 10% of naive CD4(+) T cells. This proliferation is not due to an increase in the costimulatory capacity of DCs, but is dependent on apoptotic cell-associated material processed through an endo-lysosomal pathway and presented on DC MHC class II molecules. Autologous CD4(+) T cells stimulated with apoptotic cell-loaded DCs exhibit suppressive capacities. However, in the presence of bacterial lipopolysaccharide, apoptotic cell-loaded DCs induce the generation of IL-17-producing cells. Thus, apoptotic cell engulfment by DCs may lead to increased autologous responses, initially generating CD4(+) T cells with suppressive capacities able to differentiate into Th17 cells in the presence of a bacterial danger signal such as LPS.

TLR3-responsive, XCR1+, CD141(BDCA-3)+/CD8α+-equivalent dendritic cells uncovered in healthy and simian immunodeficiency virus-infected rhesus macaques.

In mice, CD8α(+) myeloid dendritic cells (mDC) optimally cross-present Ags to CD8(+) T cells and respond strongly to TLR3 ligands. Although equivalent DC have been identified by comparative genomic analysis and functional studies in humans as XCR1(+)CD141 (BDCA-3)(+)Clec9A(+)cell adhesion molecule 1(+) mDC, and in sheep as CD26(+) mDC, these cells remained elusive in nonhuman primates. To remedy this situation, we delineated precisely DC and monocyte populations by 12-color flow cytometry and transcriptomic analyses in healthy rhesus macaques. We identified a new mDC population, with strong phenotypic and transcriptional homology to human CD141(+) and murine CD8α(+) mDC, including XCR1 membrane expression as a conserved specific marker. In contrast, high CD11c expression was not characteristic of mDC in macaques, but of CD16(+) monocytes. Like their human and murine homologs, simian XCR1(+) mDC had much stronger responses to TLR3 stimulation than other myeloid cells. The importance of this new mDC population was tested in SIV(mac251) infection, the most relevant animal model for pathogenic HIV-1 infection and vaccination. This population increased sharply and transiently during acute infection, but was reduced in blood and spleen during advanced disease. The identification of XCR1(+) mDC in rhesus macaques opens new avenues for future preclinical vaccinal studies and highlights XCR1 as a prime candidate for targeted vaccine delivery.

Memory CD8(+) T cells elicited by HIV-1 lipopeptide vaccines display similar phenotypic profiles but differences in term of magnitude and multifunctionality compared with FLU- or EBV-specific memory T cells in humans.

Differentiation marker, multifunctionality and magnitude analyses of specific-CD8(+) memory T cells are crucial to improve development of HIV vaccines designed to generate cell-mediated immunity. Therefore, we fully characterized the HIV-specific CD8(+) T cell responses induced in volunteers vaccinated with HIV lipopeptide vaccines for phenotypic markers, tetramer staining, cytokine secretion, and cytotoxic activities. The frequency of ex vivo CD8(+) T cells elicited by lipopeptide vaccines is very rare and central-memory phenotype and functions of these cells were been shown to be important in AIDS immunity. So, we expanded them using specific peptides to compare the memory T cell responses induced in volunteers by HIV vaccines with responses to influenza (FLU) or Epstein Barr virus (EBV). By analyzing the differentiation state of IFN-γ-secreting CD8(+) T cells, we found a CCR7(-)CD45RA(-)CD28(+int)/CD28(-) profile (>85%) belonging to a subset of intermediate-differentiated effector T cells for HIV, FLU, and EBV. We then assessed the quality of the response by measuring various T cell functions. The percentage of single IFN-γ T cell producers in response to HIV was 62% of the total of secreting T cells compared with 35% for FLU and EBV, dual and triple (IFN-γ/IL-2/CD107a) T cell producers could also be detected but at lower levels (8% compared with 37%). Finally, HIV-specific T cells secreted IFN-γ and TNF-α, but not the dual combination like FLU- and EBV-specific T cells. Thus, we found that the functional profile and magnitude of expanded HIV-specific CD8(+) T precursors were more limited than those of to FLU- and EBV-specific CD8(+) T cells. These data show that CD8(+) T cells induced by these HIV vaccines have a similar differentiation profile to FLU and EBV CD8(+) T cells, but that the vaccine potency to induce multifunctional T cells needs to be increased in order to improve vaccination strategies.

Human inflammatory dendritic cells induce Th17 cell differentiation.

Dendritic cells (DCs) are critical regulators of immune responses. Under noninflammatory conditions, several human DC subsets have been identified. Little is known, however, about the human DC compartment under inflammatory conditions. Here, we characterize a DC population found in human inflammatory fluids that displayed a phenotype distinct from macrophages from the same fluids and from steady-state lymphoid organ and blood DCs. Transcriptome analysis showed that they correspond to a distinct DC subset and share gene signatures with in vitro monocyte-derived DCs. Moreover, human inflammatory DCs, but not inflammatory macrophages, stimulated autologous memory CD4(+) T cells to produce interleukin-17 and induce T helper 17 (Th17) cell differentiation from naive CD4(+) T cells through the selective secretion of Th17 cell-polarizing cytokines. We conclude that inflammatory DCs represent a distinct human DC subset and propose that they are derived from monocytes and are involved in the induction and maintenance of Th17 cell responses.