DC-T Cell Interactions Research Articles

How type-2 dendritic cells induce Th2 differentiation: Instruction, repression, or fostering T cell-T cell communication?

Allergic disease is caused by the activation of allergen-specific CD4+ type-2 T follicular helper cells (Tfh2) and T helper 2 (Th2) effector cells that secrete the cytokines IL-4, IL-5, IL-9, and IL-13 upon allergen encounter, thereby inducing IgE production by B cells and tissue inflammation. While it is accepted that the priming and differentiation of naïve CD4+ T cells into Th2 requires allergen presentation by type 2 dendritic cells (DC2s), the underlying signals remain unidentified. In this review we focus on the interaction between allergen-presenting DC2s and naïve CD4+ T cells in lymph node (LN), and the potential mechanisms by which DC2s might instruct Th2 differentiation. We outline recent advances in characterizing DC2 development and heterogeneity. We review mechanisms of allergen sensing and current proposed mechanisms of Th2 differentiation, with specific consideration of the role of DC2s and how they might contribute to each mechanism. Finally, we assess recent publications reporting a detailed analysis of DC-T cell interactions in LNs and how they support Th2 differentiation. Together, these studies are starting to shape our understanding of this key initial step of the allergic immune response.

Chemokines and Cytokines in Immunotherapy of Melanoma and Other Tumors: From Biomarkers to Therapeutic Targets.

Chemokines and cytokines represent an emerging field of immunotherapy research. They are responsible for the crosstalk and chemoattraction of immune cells and tumor cells. For instance, CXCL9/10/11 chemoattract effector CD8+ T cells to the tumor microenvironment, making an argument for their promising role as biomarkers for a favorable outcome. The cytokine Interleukin-15 (IL-15) can promote the chemokine expression of CXCR3 ligands but also XCL1, contributing to an important DC-T cell interaction. Recruited cytotoxic T cells can be clonally expanded by IL-2. Delivering or inducing these chemokines and cytokines can result in tumor shrinkage and might synergize with immune checkpoint inhibition. In addition, blocking specific chemokine and cytokine receptors such as CCR2, CCR4 or Il-6R can reduce the recruitment of tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs) or regulatory T cells (Tregs). Efforts to target these chemokines and cytokines have the potential to personalize cancer immunotherapy further and address patients that are not yet responsive because of immune cell exclusion. Targeting cytokines such as IL-6 and IL-15 is currently being evaluated in clinical trials in combination with immune checkpoint-blocking antibodies for the treatment of metastatic melanoma. The improved overall survival of melanoma patients might outweigh potential risks such as autoimmunity. However, off-target toxicity needs to be elucidated.

Insights into dendritic cell maturation during infection with application of advanced imaging techniques.

Dendritic cells (DCs) are crucial for the initiation and regulation of adaptive immune responses. When encountering immune stimulus such as bacterial and viral infection, parasite invasion and dead cell debris, DCs capture antigens, mature, acquire immunostimulatory activity and transmit the immune information to naïve T cells. Then activated cytotoxic CD8+ T cells directly kill the infected cells, while CD4+ T helper cells release cytokines to aid the activity of other immune cells, and help B cells produce antibodies. Thus, detailed insights into the DC maturation process are necessary for us to understand the working principle of immune system, and develop new medical treatments for infection, cancer and autoimmune disease. This review summarizes the DC maturation process, including environment sensing and antigen sampling by resting DCs, antigen processing and presentation on the cell surface, DC migration, DC-T cell interaction and T cell activation. Application of advanced imaging modalities allows visualization of subcellular and molecular processes in a super-high resolution. The spatiotemporal tracking of DCs position and migration reveals dynamics of DC behavior during infection, shedding novel lights on DC biology.

Actions of Dendritic Cells in the Kidney during Hypertension.

The immune response plays a critical role in the pathogenesis of hypertension, and immune cell populations can promote blood pressure elevation via actions in the kidney. Among these cell lineages, dendritic cells (DCs), the most potent antigen-presenting cells, play a central role in regulating immune response during hypertension and kidney disease. DCs have different subtypes, and renal DCs are comprised of the CD103+ CD11b- and CD103- CD11b+ subsets. DCs become mature and express costimulatory molecules on their surface once they encounter antigen. Isolevuglandin-modified proteins function as antigens to activate DCs and trigger them to stimulate T cells. Activated T cells accumulate in the hypertensive kidney, release effector cytokines, promote renal oxidative stress, and promote renal salt and water retention. Individual subsets of activated T cells can secrete tumor necrosis factor-alpha, interleukin-17A, and interferon-gamma, each of which has augmented the elevation of blood pressure in hypertensive models by enhancing renal sodium transport. Fms-like tyrosine kinase 3 ligand-dependent classical DCs are required to sustain the full hypertensive response, but C-X3 -C chemokine receptor 1 positive DCs do not regulate blood pressure. Excess sodium enters the DC through transporters to activate DCs, whereas the ubiquitin editor A20 in dendritic cells constrains blood pressure elevation by limiting T cell activation. By contrast, activation of the salt sensing kinase, serum/glucocorticoid kinase 1 in DCs exacerbates salt-sensitive hypertension. This article discusses recent studies illustrating mechanisms through which DC-T cell interactions modulate levels of pro-hypertensive mediators to regulate blood pressure via actions in the kidney. © 2022 American Physiological Society. Compr Physiol 12:1-15, 2022.

Transcriptional Profiling of Leishmania infantum Infected Dendritic Cells: Insights into the Role of Immunometabolism in Host-Parasite Interaction.

Leishmania parasites are capable of effectively invading dendritic cells (DCs), a cell population orchestrating immune responses against several diseases, including leishmaniasis, by bridging innate and adaptive immunity. Leishmania on the other hand has evolved various mechanisms to subvert DCs activation and establish infection. Thus, the transcriptional profile of DCs derived from bone marrow (BMDCs) that have been infected with Leishmania infantum parasite or of DCs exposed to chemically inactivated parasites was investigated via RNA sequencing, aiming to better understand the host–pathogen interplay. Flow cytometry analysis revealed that L. infantum actively inhibits maturation of not only infected but also bystander BMDCs. Analysis of double-sorted L. infantum infected BMDCs revealed significantly increased expression of genes mainly associated with metabolism and particularly glycolysis. Moreover, differentially expressed genes (DEGs) related to DC-T cell interactions were also found to be upregulated exclusively in infected BMDCs. On the contrary, transcriptome analysis of fixed parasites containing BMDCs indicated that energy production was mediated through TCA cycle and oxidative phosphorylation. In addition, DEGs related to differentiation of DCs leading to activation and differentiation of Th17 subpopulations were detected. These findings suggest an important role of metabolism on DCs-Leishmania interplay and eventually disease establishment.

ILC1-like NK cells as matchmakers for DC-T cell interactions

Both innate and adaptive immunity are orchestrated by multiple cell types, specialized cell lineages, and their spatiotemporal encounters. It is thought that adaptive-like NK cell responses to viral infection mainly involve circulating bona fide NK cells. In this issue of Immunity, Flommersfeld etal. (2021) identify a splenic-resident ILC1-like NK cell subset that facilitates CD8+ Tcell-DC interactions during anti-viral defense.

Reduced CXCL1 production by endogenous IL-37 expressing dendritic cells does not affect T cell activation.

The dendritic cell (DC)-derived cytokine profile contributes to naive T cell differentiation, thereby directing the immune response. IL-37 is a cytokine with anti-inflammatory characteristics that has been demonstrated to induce tolerogenic properties in DC. In this study we aimed to evaluate the influence of IL-37 on DC-T cell interaction, with a special focus on the role of the chemokine CXCL1. DC were cultured from bone marrow of human IL-37 transgenic (hIL-37Tg) or WT mice. The phenotype of unstimulated and LPS-stimulated DC was analyzed (co-stimulatory molecules and MHCII by flow cytometry, cytokine profile by RT-PCR and ELISA), and T cell stimulatory capacity was assessed in mixed lymphocyte reaction. The role of CXCL1 in T cell activation was analyzed in T cell stimulation assays with anti-CD3 or allogeneic DC. The expression of the co-stimulatory molecules CD40, CD80 and CD86, and of MHCII in LPS-stimulated DC was not affected by endogenous expression of IL-37, whereas LPS-stimulated hIL-37Tg DC produced less CXCL1 compared to LPS-stimulated WT DC. T cell stimulatory capacity of LPS-matured hIL-37Tg DC was comparable to that of WT DC. Recombinant mouse CXCL1 did not increase T cell proliferation either alone or in combination with anti-CD3 or allogeneic DC, nor did CXCL1 affect the T cell production of interferon-γ and IL-17. Endogenous IL-37 expression does not affect mouse DC phenotype or subsequent T cell stimulatory capacity, despite a reduced CXCL1 production. In addition, we did not observe an effect of CXCL1 in T cell proliferation or differentiation.

Dendritic Cells Supply CD4+ T Cells With L-arginine

Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis, is responsible for over 1 million deaths each year. Mycobacteria-infected dendritic cells (DCs) migrate to the lymph node to initiate adaptive immune priming, which is vital to antimycobacterial immunity. This response is intimately tied to nutrient availability – especially the amino acid L-arginine (L-ARG), metabolism of which is altered in TB patients. We have characterized a pathway utilized by immune cells to synthesize L-ARG. Loss of L-ARG synthesis in CD11c+ cells, which includes DCs, results in increased mycobacterial burden following infection in mice. To characterize the role of this pathway in DCs, we developed a co-culture system with mycobacterial-specific CD4+ T cells and bone marrow derived DCs. Using CD4+ T cells and DCs with differing capabilities of L-ARG synthesis, we found 1) DC L-ARG synthesis supports CD4+ T cell proliferation and 2) activated T cells contain DC-derived L-ARG. We hypothesize DCs “share” synthesized L-ARG to support CD4+ T cell activation when L-ARG is limiting. Our data suggest nutrient availability as a 4th signal – following antigen presentation, co-stimulation, and cytokine receptor ligation – required for T cell activation. This work expands the current model of DC-T cell interactions and provides insight into the effects of nutrient availability in immune cells.

Maturation of Monocyte-Derived DCs Leads to Increased Cellular Stiffness, Higher Membrane Fluidity, and Changed Lipid Composition.

Dendritic cells (DCs) are professional antigen-presenting cells of the immune system. Upon sensing pathogenic material in their environment, DCs start to mature, which includes cellular processes, such as antigen uptake, processing and presentation, as well as upregulation of costimulatory molecules and cytokine secretion. During maturation, DCs detach from peripheral tissues, migrate to the nearest lymph node, and find their way into the correct position in the net of the lymph node microenvironment to meet and interact with the respective T cells. We hypothesize that the maturation of DCs is well prepared and optimized leading to processes that alter various cellular characteristics from mechanics and metabolism to membrane properties. Here, we investigated the mechanical properties of monocyte-derived dendritic cells (moDCs) using real-time deformability cytometry to measure cytoskeletal changes and found that mature moDCs were stiffer compared to immature moDCs. These cellular changes likely play an important role in the processes of cell migration and T cell activation. As lipids constitute the building blocks of the plasma membrane, which, during maturation, need to adapt to the environment for migration and DC-T cell interaction, we performed an unbiased high-throughput lipidomics screening to identify the lipidome of moDCs. These analyses revealed that the overall lipid composition was significantly changed during moDC maturation, even implying an increase of storage lipids and differences of the relative abundance of membrane lipids upon maturation. Further, metadata analyses demonstrated that lipid changes were associated with the serum low-density lipoprotein (LDL) and cholesterol levels in the blood of the donors. Finally, using lipid packing imaging we found that the membrane of mature moDCs revealed a higher fluidity compared to immature moDCs. This comprehensive and quantitative characterization of maturation associated changes in moDCs sets the stage for improving their use in clinical application.

Tyrosine Kinase 2 Signalling Drives Pathogenic T cells in Colitis.

Background and AimsTyrosine kinase 2 [TYK2] is required for the signalling of key cytokines in the pathogenesis of inflammatory bowel disease [IBD]. We assessed the efficacy of a novel selective TYK2 inhibitor [TYK2i] in experimental colitis, using pharmacological and genetic tools.MethodsAt onset of T cell transfer colitis, RAG1-/- mice received vehicle or TYK2i daily by oral gavage. T cells lacking TYK2 kinase activity [TYK2KE] were used to confirm selectivity of the inhibitor. To this end, RAG1-/- or RAG1-/-TYK2KE animals were transferred with either wild type [WT] or TYK2KE-CD45RBhigh colitogenic T cells. Loss of body weight, endoscopic disease, the disease activity index [DAI], and histopathology scores were recorded. Tissues were analysed ex vivo for lymphocyte populations by flow cytometry. The impact of TYK2 inhibition on human DC-T cell interactions were studied using autologous Revaxis specific T cell assays.ResultsTYK2i [70 mg/kg] prevented weight loss and limited endoscopic activity during T cell transfer colitis. TYK2i [70 mg/kg] decreased DAI. Whereas transfer of WT T cells into RAG-/-TYK2KE hosts induced colitis, TYK2KE T cells transferred into RAG1-/-TYK2KErecipients failed to do so. Ex vivo analysis showed a decrease in colon tissue Th1 cells and an increase in Th17 cells upon transfer of TYK2KE-CD45RBhigh cells. In human antigen-triggered T cells, TYK2i displayed reduced Th1 differentiation, similar to murine Th1 cells.ConclusionsOral administration of TYK2i, as well as transfer of T cells lacking TYK2 activity, reduced human Th1 differentiation and ameliorated the course of murine T cell transfer colitis. We conclude that TYK2 is a promising drug target for the treatment of IBD.

The Impact of Malaria Parasites on Dendritic Cell-T Cell Interaction.

Malaria is caused by apicomplexan parasites of the genus Plasmodium. While infection continues to pose a risk for the majority of the global population, the burden of disease mainly resides in Sub-Saharan Africa. Although immunity develops against disease, this requires years of persistent exposure and is not associated with protection against infection. Repeat infections occur due to the parasite's ability to disrupt or evade the host immune responses. However, despite many years of study, the mechanisms of this disruption remain unclear. Previous studies have demonstrated a parasite-induced failure in dendritic cell (DCs) function affecting the generation of helper T cell responses. These T cells fail to help B cell responses, reducing the production of antibodies that are necessary to control malaria infection. This review focuses on our current understanding of the effect of Plasmodium parasite on DC function, DC-T cell interaction, and T cell activation. A better understanding of how parasites disrupt DC-T cell interactions will lead to new targets and approaches to reinstate adaptive immune responses and enhance parasite immunity.

Role of syndecan-1 in the interaction between dendritic cells and T cells.

Syndecan-1 (Sdc-1) is a heparan sulfate proteoglycan that can bind cytokines and chemokines via its heparan sulfate side chains, and has immunomodulatory properties in experimental models. Sdc-1 expression has been reported on dendritic cells (DC) and T cells. The potential role of Sdc-1 in DC-T cell interaction has not been investigated yet. We postulate that Sdc-1 is involved in DC-T cell interaction and may influence graft survival in an allogeneic transplant model. Sdc-1 expression on bone marrow-derived DC and T cells was analyzed by flow cytometry. Unstimulated and LPS stimulated Sdc-1 deficient DC were evaluated in vitro for phenotype and stimulatory capacity in mixed lymphocyte reaction. Sdc-1 deficient T cells were evaluated for proliferative capacity and differentiation in a mixed lymphocyte reaction and a proliferation assay. Allograft survival was evaluated in a fully MHC mismatched heterotopic heart transplant model, with either Sdc-1 deficient donors or recipients. Sdc-1 was expressed on the cell surface of unstimulated and LPS matured DC. Sdc-1 deficiency had no effect on expression of co-stimulatory molecules, cytokine production or T cell stimulatory capacity as compared to WT DC. Sdc-1 expression was not detectable on WT T cells, although intracellular Sdc-1 expression could be demonstrated after ConA activation. Sdc-1 deficient T cells showed reduced proliferation upon DC or ConA stimulation and reduced IL-17 production upon ConA stimulation, compared to WT T cells. Sdc-1 deficiency of either allograft or recipient did not prolong allograft survival. In conclusion, Sdc-1 is expressed on the cell surface of DC, where its absence does not affect DC phenotype or T cell stimulatory capacity. Sdc-1 is intracellularly expressed in ConA activated T cells. Sdc-1 deficiency in T cells results in a reduced proliferative response in vitro, as induced by DC and ConA. Sdc-1 deficiency in donor or recipient does not affect allograft survival.

Immunological function of Foxo6 in hypersensitive immune reaction

Abstract Forkhead box O(FoxO) is a transcription factor which is involved in cell cycle progression, cell survival and DNA-repair. Dendritic cells(DCs) are professional antigen-presenting cells which present the antigens to T lymphocytes and regulate the adaptive immunity. Previous studies indicated that FoxO1 and 3 are plays a critical role in DC maturation and DC-T cell interaction. FoxO6, a member of FoxO family, is less attended than other FoxO families, because limited expression region of FoxO6. Also, the effect of FoxO6 is still unknown. Here, we investigated the effect of FoxO6 in dendritic cells. Phosphorylated FoxO6 is increased and acetylated FoxO6 is decreased during dendritic cell differentiation. Moreover, deficiency of Foxo6 altered antigen capacity of dendiritc cells. Therefore, we expect that FoxO6 has important role in DC differentiation and maturation, and will further investigate the functions and the mechanisms of FoxO6 on DC. And alteration of FoxO6 expression level had effect on DCs maturation.

TCR Repertoire Clonality Analysis and Transcriptome Analyses of Immune Infiltrates in Patients with Langerhans Cell Histiocytosis Can Define Prognostic Biomarkers for Future Therapeutic Development

Langerhans Cell Histiocytosis (LCH) is a myeloproliferative disorder, most common in children, with an incidence of approximately 5 cases per million children and 1/10,000 live births per year - similar to the frequency of Hodgkin's lymphoma and AML in children. LCH lesions are comprised of clonal pathologic CD207+ dendritic cells (DCs) harboring mutually exclusive genomic alterations of MAPK pathway members along with a large inflammatory infiltrate comprised of macrophages, multinucleated giant cells, lymphocytes, and eosinophils that do not carry MAPK mutations. Mass cytometry revealed that in systemic LCH lesions, T lymphocytes are the most abundant cellular subsets among immune infiltrates and exhibit an exhausted phenotype characterized by expression of immune inhibitory receptors. Since inflammatory infiltrate composed of cells without MAPK pathway mutation is characteristic of LCH, it is likely that the pathogenic DCs in LCH mediate some of the pathologic manifestations through DC-T cell interactions. However, properties of tumor infiltrating T lymphocytes (TILs) in LCH are poorly understood, In this study we performed Bulk TCR alpha/ beta repertoire profiling using the SMARTer TCR a/b Profiling Kit (Takara Bio ) to identify the CDR3 and full length clonotypes in sorted CD8, CD4 and CD4 CD25 compartments isolated from lesions that were stimulated as well the repertoire from the matching white blood cells. We found that in the sorted CD8 cells and CD4 cells from all patient lesions, there was a characteristic clonality shift where-in the repertoire in the lesions were clonally expanded, and interestingly some of the V, J genes were shared among the patient lesions, In addition to changes in the TCR repertoire, we performed bulk Transcriptome analyses to characterize the functional nature of the T-cell infiltrates, and we find that genes responsible for calcium mobilization and mitochondrial metabolism are significantly downregulated in LCH TILs, even after TCR stimulation. RANKL (encoding receptor activator of nuclear factor kappa-B ligand or tumor necrosis factor ligand superfamily member 11) expression, which is solely dependent on TCR activation‐induced calcium mobilization, is also downregulated in the LCH TILs. RANKL is widely known as a modulator of immune cell function by virtue of influencing the survival and T cell-stimulatory capacity of DCs. Impaired calcium mobilization and mitochondrial metabolism might explain the exhausted phenotype we observe in the LCH TILs. We are currently investigating whether the clonal signatures identified by TCR sequencing in the LCH TILs can be used for prognostic purposes, and the T cell functional states can also be exploited to identify biomarkers that can be used to stratify LCH patients for therapy. Disclosures No relevant conflicts of interest to declare.

Forkhead box O 6 modulates immunological functions of Dendritic cells

Abstract Forkhead box O (FoxO) is a transcription factor which is involved in cell cycle progression, cell survival and DNA-repair. Dendritic cells (DCs) are professional antigen-presenting cells which present the antigens to T lymphocytes and regulate the adaptive immunity. Previous studies indicated that FoxO1 and 3 are plays a critical role in DC maturation and DC-T cell interaction. FoxO6, a member of FoxO family, is less attended than other FoxO families, because limited expression region of FoxO6. Also, the effect of FoxO6 is still unknown. Here, we investigated the effect of FoxO6 in dendritic cells. Out data suggest that FoxO6 is expressed in murine dendritic cells. Moreover, phosphorylated FoxO6 is increased and acetylated FoxO6 is decreased during dendritic cell differentiation. We expect that FoxO6 has important role in DC differentiation and maturation, and will further investigate the functions and the mechanisms of FoxO6 on DC. And alteration of FoxO6 expression level had effect on DCs maturation. [This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2014R1A1A1008053), Korea.]

Intranodal dendritic cell relocalization during inflammation impacts T cell immunity

Abstract Conventional dendritic cells (cDCs) are the critical antigen-presenting cells that initiate adaptive immunity in response to external inflammatory stimuli. We have previously shown that LN-resident cDC2s, a DC subset critical for generating CD4 T cell responses, reside in regions highly proximal to the lymphatic sinuses, enabling superior acquisition of draining soluble and particulate antigens. However, given that this peripheral positioning is distal from the deep LN paracortex and the T cell zone, we hypothesized that for optimal generation of adaptive immunity, LN-resident cDC2s must migrate intranodally from peripheral sites into the deep T zone in order to engage in cognate DC-T cell interactions during priming. Here, we show that s.c immunization with TLR-agonists, as well as infection with West Nile Virus, induces rapid relocalization of cDC2s into the deep T zone of the LN. This cDC2 relocalization requires Type 1 interferon in some, but not all, adjuvant immunizations, and is predominantly driven by increased CCR7 expression on cDCs after maturation. When lacking CCR7, LN-resident cDC2s failed to reposition to the T cell zone across multiple adjuvant comparisons, and this in turn led to a marked reduction in the activation and proliferation of CD4+ T cells. A decrease in the differentiation of Tfh cells was also observed, suggesting a possible impact on humoral immunity. Collectively, this work identifies a novel CCR7-mediated spatial reorganization of LN-resident cDC2s during inflammation, independent of peripheral migratory DCs, and its role in the generation of adaptive immunity.

Dendritic Cells and T Cells Interact Within Murine Afferent Lymphatic Capillaries.

Afferent lymphatic vessels contribute to immunity by transporting antigen and leukocytes to draining lymph nodes (LNs) and are emerging as new players in the regulation of peripheral tolerance. Performing intravital microscopy in inflamed murine ear skin we found that migrating dendritic cells (DCs) and antigen-experienced effector T cells spend considerable time arresting or clustering within afferent lymphatic capillaries. We also observed that intralymphatic T cells frequently interacted with DCs. When imaging polyclonal T cells during an ongoing contact-hypersensitivity response, most intralymphatic DC-T cell interactions were short-lived. Conversely, during a delayed-type-hypersensitivity response, cognate antigen-bearing DCs engaged in long-lived MHCII-(I-A/I-E)-dependent interactions with antigen-specific T cells. Long-lived intralymphatic DC-T cell interactions reduced the speed of DC crawling but did not delay overall DC migration to draining LNs. While further consequences of these intralymphatic interactions still need to be explored, our findings suggest that lymphatic capillaries represent a unique compartment in which adaptive immune interaction and modulation occur.

Dendritic cells, T cells and their interaction in rheumatoid arthritis.

Dendritic cells (DCs) are the key professional antigen-presenting cells which bridge innate and adaptive immune responses, inducing the priming and differentiation of naive to effector CD4+ T cells, the cross-priming of CD8+ T cells and the promotion of B cell antibody responses. DCs also play a critical role in the maintenance of immune homeostasis and tolerance. DC-T cell interactions underpin the generation of an autoimmune response in rheumatoid arthritis (RA). Here we describe the function of DCs and review evidence for DC and T cell involvement in RA pathogenesis, in particular through the presentation of self-peptide by DCs that triggers differentiation and activation of autoreactive T cells. Finally, we discuss the emerging field of targeting the DC-T cell interaction for antigen-specific immunotherapy of RA.

Enriched Cd141+ DCs in the joint are transcriptionally distinct, activated, and contribute to joint pathogenesis.

CD141+ DC are implicated in antiviral and antitumor immunity. However, mechanistic studies in autoimmune disease are limited. This is the first study to our knowledge examining CD141+ DC in autoimmune disease, specifically inflammatory arthritis (IA). We identified significant enrichment of CD141+ DC in the inflamed synovial joint, which were transcriptionally distinct from IA and healthy control (HC) blood CD141+ DC and significantly more activated, and they exhibited increased responsiveness to TLR3. Synovial CD141+ DC represent a bone fide CD141+ DC population that is distinct from CD1c+ DC. Synovial CD141+ DC induced higher levels of CD4+ and CD8+ T cell activation compared with their peripheral blood counterparts, as made evident by expression of IFN-γ, TNF-α, and granulocyte-macrophage CSF (GMCSF). Autologous synovial CD141+ DC cocultures also induce higher levels of these cytokines, further highlighting their contribution to synovial inflammation. Synovial CD141+ DC-T cell interactions had the ability to further activate synovial fibroblasts, inducing adhesive and invasive pathogenic mechanisms. Furthermore, we identify a mechanism in which synovial CD141+ DC are activated, via ligation of the hypoxia-inducible immune-amplification receptor TREM-1, which increased synovial CD141+ DC activation, migratory capacity, and proinflammatory cytokines. Thus, synovial CD141+ DC display unique mechanistic and transcriptomic signatures, which are distinguishable from blood CD141+ DC and can contribute to synovial joint inflammation.

World Arthritis Day 2018 ‐ Perspectives on Rheumatic musculoskeletal diseases

World Arthritis Day 2018 ‐ Perspectives on Rheumatic musculoskeletal diseases