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.

Dendritic cells (DCs) play critical roles in immune-mediated kidney diseases. Little is known, however, about DC subsets in human chronic kidney disease, with previous studies restricted to a limited set of pathologies and to using immunohistochemical methods. In this study, we developed novel protocols for extracting renal DC subsets from diseased human kidneys and identified, enumerated, and phenotyped them by multicolor flow cytometry. We detected significantly greater numbers of total DCs as well as CD141^hiand CD1c⁺myeloid DC (mDCs) subsets in diseased biopsies with interstitial fibrosis than diseased biopsies without fibrosis or healthy kidney tissue. In contrast, plasmacytoid DC numbers were significantly higher in the fibrotic group compared with healthy tissue only. Numbers of all DC subsets correlated with loss of kidney function, recorded as estimated glomerular filtration rate. CD141^hiDCs expressed C-type lectin domain family 9 member A (CLEC9A), whereas the majority of CD1c⁺DCs lacked the expression of CD1a and DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN), suggesting these mDC subsets may be circulating CD141^hiand CD1c⁺blood DCs infiltrating kidney tissue. Our analysis revealed CLEC9A⁺and CD1c⁺cells were restricted to the tubulointerstitium. Notably, DC expression of the costimulatory and maturation molecule CD86 was significantly increased in both diseased cohorts compared with healthy tissue. Transforming growth factor-β levels in dissociated tissue supernatants were significantly elevated in diseased biopsies with fibrosis compared with nonfibrotic biopsies, with mDCs identified as a major source of this profibrotic cytokine. Collectively, our data indicate that activated mDC subsets, likely recruited into the tubulointerstitium, are positioned to play a role in the development of fibrosis and, thus, progression to chronic kidney disease.

Human blood myeloid DCs can be subdivided into CD1c (BDCA‐1)⁺ and CD141 (BDCA‐3)⁺ 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.

Systemic lupus erythematosus (SLE) is a systemic, autoimmune disease that can involve virtually any organ of the body. Lupus nephritis (LN), the clinical manifestation of this disease in the kidney, is one of the most common and severe outcomes of SLE. Although a key pathological hallmark of LN is glomerular inflammation and damage, tubulointerstitial lesions have been recognized as an important component in the pathology of LN. Renal tubular epithelial cells are resident cells in the tubulointerstitium that have been shown to play crucial roles in various acute and chronic kidney diseases. In this context, recent progress has been made in examining the functional role of tubular epithelial cells in LN pathogenesis. This review summarizes recent advances in our understanding of renal tubular epithelial cells in LN, the potential role of tubular epithelial cells as biomarkers in the diagnosis, prognosis, and treatment of LN, and the future therapeutic potential of targeting the tubulointerstitium for the treatment of patients with LN.