Cytokines produced by dendritic cells (DCs) can largely determine the direction of immunity. Transcriptional analysis revealed that besides IL-15, IL-32 was the only other cytokine expressed by human ...Langerhans cells. IL-32 is a human cytokine that exists in four main isoforms. Currently, little is known about the regulation and function of the various IL-32 isoforms. In this study, we found that IL-15 is a potent inducer of IL-32α in DCs. Because IL-15 promotes NK cell activation, we investigated the interplay between IL-32 and IL-15 and their role in NK cell activity. We show that IL-32α acts on NK cells to inhibit IL-15-mediated STAT5 phosphorylation and to suppress their IL-15-induced effector molecule expression and cytolytic capacity. IL-32α also acted on DCs by downregulating IL-15-induced IL-18 production, an important cytokine in NK cell activity. Blocking IL-32α during DC:NK cell coculture enhanced NK cell effector molecule expression as well as their cytolytic capacity. Taken together, our findings suggest a feedback inhibition of IL-15-mediated NK cell activity by IL-32α.
The skin immune system includes a complex network of dendritic cells (DCs). In addition to generating cellular and humoral immunity against pathogens, skin DCs are involved in tolerogenic mechanisms ...that maintain immune homeostasis and in pathogenic chronic inflammation in which immune responses are unrestrained. Harnessing DC function by directly targeting DC‐derived molecules or by selectively modulating DC subsets is a novel strategy for ameliorating inflammatory diseases. In this short review, we discuss recent advances in understanding the functional specialization of skin DCs and the potential implication for future DC‐based therapeutic strategies.
Little is known about the functional differences between the human skin myeloid dendritic cell (DC) subsets, epidermal CD207
+ Langerhans cells (LCs) and dermal CD14
+ DCs. We showed that CD14
+ DCs ...primed CD4
+ T cells into cells that induce naive B cells to switch isotype and become plasma cells. In contrast, LCs preferentially induced the differentiation of CD4
+ T cells secreting T helper 2 (Th2) cell cytokines and were efficient at priming and crosspriming naive CD8
+ T cells. A third DC population, CD14
−CD207
−CD1a
+ DC, which resides in the dermis, could activate CD8
+ T cells better than CD14
+ DCs but less efficiently than LCs. Thus, the human skin displays three DC subsets, two of which, i.e., CD14
+ DCs and LCs, display functional specializations, the preferential activation of humoral and cellular immunity, respectively.
Granulomas are complex cellular structures composed predominantly of macrophages and lymphocytes that function to contain and kill invading pathogens. Here, we investigated the single-cell phenotypes ...associated with antimicrobial responses in human leprosy granulomas by applying single-cell and spatial sequencing to leprosy biopsy specimens. We focused on reversal reactions (RRs), a dynamic process whereby some patients with disseminated lepromatous leprosy (L-lep) transition toward self-limiting tuberculoid leprosy (T-lep), mounting effective antimicrobial responses. We identified a set of genes encoding proteins involved in antimicrobial responses that are differentially expressed in RR versus L-lep lesions and regulated by interferon-γ and interleukin-1β. By integrating the spatial coordinates of the key cell types and antimicrobial gene expression in RR and T-lep lesions, we constructed a map revealing the organized architecture of granulomas depicting compositional and functional layers by which macrophages, T cells, keratinocytes and fibroblasts can each contribute to the antimicrobial response.
The immunopathogenesis of psoriasis, a common chronic inflammatory disease of the skin, is incompletely understood. Here we demonstrate, using a combination of single cell and spatial RNA sequencing, ...IL-36 dependent amplification of IL-17A and TNF inflammatory responses in the absence of neutrophil proteases, which primarily occur within the supraspinous layer of the psoriatic epidermis. We further show that a subset of SFRP2
fibroblasts in psoriasis contribute to amplification of the immune network through transition to a pro-inflammatory state. The SFRP2
fibroblast communication network involves production of CCL13, CCL19 and CXCL12, connected by ligand-receptor interactions to other spatially proximate cell types: CCR2
myeloid cells, CCR7
LAMP3
dendritic cells, and CXCR4 expressed on both CD8
Tc17 cells and keratinocytes, respectively. The SFRP2
fibroblasts also express cathepsin S, further amplifying inflammatory responses by activating IL-36G in keratinocytes. These data provide an in-depth view of psoriasis pathogenesis, which expands our understanding of the critical cellular participants to include inflammatory fibroblasts and their cellular interactions.
The dendritic cell (DC) system of antigen-presenting cells controls immunity and tolerance. DCs initiate and regulate immune responses in a manner that depends on signals they receive from microbes ...and their cellular environment. They allow the immune system to make qualitatively distinct responses against different microbial infections. DCs are composed of subsets that express different microbial receptors and express different surface molecules and cytokines. Our studies lead us to propose that interstitial (dermal) DCs preferentially activate humoral immunity, whereas Langerhans cells preferentially induce cellular immunity. Alterations of the DC system result in diseases such as autoimmunity, allergy, and cancer. Conversely, DCs can be exploited for vaccination, and novel vaccines that directly target DCs in vivo are being designed.
Immunity results from a complex interplay between the antigen‐non‐specific innate immune system and the antigen‐specific adaptive immune system. The cells and molecules of the innate system employ ...non‐clonal recognition receptors including lectins, Toll‐like receptors, NOD‐like receptors, and helicases. B and T lymphocytes of the adaptive immune system employ clonal receptors recognizing antigens or their derived peptides in a highly specific manner. An essential link between innate and adaptive immunity is provided by dendritic cells (DCs). DCs can induce such contrasting states as immunity and tolerance. The recent years have brought a wealth of information on the biology of DCs revealing the complexity of this cell system. Indeed, DC plasticity and subsets are prominent determinants of the type and quality of elicited immune responses. In this article, we summarize our recent studies aimed at a better understanding of the DC system to unravel the pathophysiology of human diseases and design novel human vaccines.
“A properly functioning adaptive immune system signifies the best features of life. It is diverse beyond compare, tolerant without fail, and capable of behaving appropriately with a myriad of ...infections and other challenges. Dendritic cells (DCs) are required to explain how this remarkable system is energized and directed.” This is a quote by one of the greatest immunologists our community has ever known, and the father of dendritic cells, Ralph Steinman. Steinman's discovery of DCs in 1973 and his subsequent research opened a new field of study within immunology: DC biology and in particular the role of DCs in immune regulation in health and disease. Here, I review themes from our work and others on the complex network of dendritic cells in the skin and discuss the significance of skin DCs in understanding aspects of host defense against infections, the pathology of inflammatory skin diseases, and speculate on the future effective immune‐based therapies.
At the crossroad between innate and adaptive immunity are the dendritic Cells (DCs), a "novel cell type." discovered in 1973 by Ralph Steinman. Although not entirely appreciated at first, it is clear ...that they play a critical role as specialized antigen-presenting cells and essential mediators in shaping immune reactivity and tolerance. Dendritic cells are now recognized as a heterogeneous group of cells in terms of cell-surface markers, anatomic location, and function adapted to protect against an array of pathogens and conditions. Importantly, these subsets are also unique to each species. While significant progress has been made on the identification and function of mouse DC subsets, much less is known about human cells. Here we review the fascinating biology of human skin DCs and describe tolerogenic principles that are critical in maintaining immune homeostasis and for controlling inflammation, as well as mechanisms that are fundamental to confer immunity. We surmise that these principles could be applied to DCs across organs, and could be harnessed for the treatment of various human autoimmune, inflammatory diseases, as well as cancer. Importantly, to leverage the relevance of basic research to the clinical setting, it is first necessary to determine the functional homology between mouse and human DCs. We discuss practical steps towards this aim.
Langerhans cells (LCs) reside in the epidermis where they are poised to mount an antimicrobial response against microbial pathogens invading from the outside environment. To elucidate potential ...pathways by which LCs contribute to host defense, we mined published LC transcriptomes deposited in GEO and the scientific literature for genes that participate in antimicrobial responses. Overall, we identified 31 genes in LCs that encode proteins that contribute to antimicrobial activity, ten of which were cross-validated in at least two separate experiments. Seven of these ten antimicrobial genes encode chemokines,
and
, which mediate both antimicrobial and inflammatory responses. Of these,
was detected in seven of nine transcriptomes and by PCR in cultured LCs. Overall, the antimicrobial genes identified in LCs encode proteins with broad antibacterial activity, including against
, which is the leading cause of skin infections. Thus, this study illustrates that LCs, consistent with their anatomical location, are programmed to mount an antimicrobial response against invading pathogens in skin.
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