CD4+ T cell responses elicited by different subsets of human skin migratory dendritic cells

Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
The Journal of Immunology (Impact Factor: 5.36). 01/2006; 175(12):7905-15. DOI: 10.4049/jimmunol.175.12.7905
Source: PubMed

ABSTRACT Skin dendritic cells (DC) are professional APC critical for initiation and control of adaptive immunity. In the present work we have analyzed the CD4+ T cell stimulatory function of different subsets of DC that migrate spontaneously from human skin explants, including CD1a+CD14- Langerhans' cells (LC), CD1a-CD14- dermal DC (DDC), and CD1a-CD14+ LC precursors. Skin migratory DC consisted of APC at different stages of maturation-activation that produced IL-10, TGF-beta1, IL-23p19, and IL-12p40, but did not release IL-12p70 even after exposure to DC1-driving stimuli. LC and DDC migrated as mature/activated APC able to stimulate allogeneic naive CD4+ T cells and to induce memory Th1 cells in the absence of IL-12p70. The potent CD4+ T cell stimulatory function of LC and DDC correlated with their high levels of expression of MHC class II, adhesion, and costimulatory molecules. The Th1-biasing function of LC and DDC depended on their ability to produce IL-23. By contrast, CD1a-CD14+ LC precursors migrated as immature-semimature APC and were weak stimulators of allogeneic naive CD4+ T cells. However, and opposite of a potential tolerogenic role of immature DC, the T cell allostimulatory and Th1-biasing function of CD14+ LC precursors increased significantly by augmenting their cell number, prolonging the time of interaction with responding T cells, or addition of recombinant human IL-23 in MLC. The data presented in this study provide insight into the function of the complex network of skin-resident DC that migrate out of the epidermis and dermis after cutaneous immunizations, pathogen infections, or allograft transplantation.

Download full-text


Available from: Geza Erdos, Apr 10, 2014
  • Source
    • "cells. Similarly , human CD1c + cDC2 in the skin can produce IL-23 [18] [97], and in the lung, potently induce Th17 cells upon Aspergillus fumigatus challenge [40]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dendritic cells (DC) are professional antigen sensing and presenting cells that link innate and adaptive immunity. Consisting of functionally specialized subsets, they form a complex cellular network capable of integrating multiple environmental signals leading to immunity or tolerance. Much of DC research so far has been carried out in mice and increasing efforts are now being devoted to translating the findings into humans and other species. Recent studies have aligned these cellular networks across species at multiple levels from phenotype, gene expression program, ontogeny and functional specializations. In this review, we focus on recent advances in the definition of bona fide DC subsets across species. The understanding of functional similarities and differences of specific DC subsets in different animals not only brings light in the field of DC biology, but also paves the way for the design of future effective therapeutic strategies targeting these cells.
    Cellular Immunology 09/2014; 291(1-2). DOI:10.1016/j.cellimm.2014.08.006 · 1.87 Impact Factor
  • Source
    • "CD14+ migratory DDC are discernable from dermis-resident CD14+ dermal macrophages through their surface expression of CD1b and CD1c (24). In a comparative analysis with CD14− DDC, CD14+ DDC were shown to be poor inducers of allogeneic T cells and to require high DC:T cell ratios for Th1 induction (25). This relative inability of CD14+ DDC to induce Th1 cells was related to their release of IL-10 and TGFβ1. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumors abuse myeloid plasticity to re-direct dendritic cell (DC) differentiation from T cell stimulatory subsets to immune-suppressive subsets that can interfere with anti-tumor immunity. Lined by a dense network of easily accessible DC the skin is a preferred site for the delivery of DC-targeted vaccines. Various groups have recently been focusing on functional aspects of DC subsets in the skin and how these may be affected by tumor-derived suppressive factors. IL-6, Prostaglandin-E2, and IL-10 were identified as factors in cultures of primary human tumors responsible for the inhibited development and activation of skin DC as well as monocyte-derived DC. IL-10 was found to be uniquely able to convert fully developed DC to immature macrophage-like cells with functional M2 characteristics in a physiologically highly relevant skin explant model in which the phenotypic and functional traits of "crawl-out" DC were studied. Mostly from mouse studies, the JAK2/STAT3 signaling pathway has emerged as a "master switch" of tumor-induced immune suppression. Our lab has additionally identified p38-MAPK as an important signaling element in human DC suppression, and recently validated it as such in ex vivo cultures of single-cell suspensions from melanoma metastases. Through the identification of molecular mechanisms and signaling events that drive myeloid immune suppression in human tumors, more effective DC-targeted cancer vaccines may be designed.
    Frontiers in Immunology 11/2013; 4:403. DOI:10.3389/fimmu.2013.00403
  • Source
    • "Whereas default Th1 induction by skin DC was previously shown to depend on IL-23 rather than IL-12p70 release [14], we found evidence for a GM-CSF and IL-4-induced release of IL-12p70 which most likely accounts for the increased induction and expansion of Th1 and high-avidity CD8+ effector T cells. Several reports have indicated that in vitro generated LC as well as primary LC and DDC, isolated from human skin, are poor IL-12p70 producers [7], [9], [47]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In cancer patients pervasive systemic suppression of Dendritic Cell (DC) differentiation and maturation can hinder vaccination efficacy. In this study we have extensively characterized migratory DC subsets from human skin and studied how their migration and T cell-stimulatory abilities were affected by conditioning of the dermal microenvironment through cancer-related suppressive cytokines. To assess effects in the context of a complex tissue structure, we made use of a near-physiological skin explant model. By 4-color flow cytometry, we identified migrated Langerhans Cells (LC) and five dermis-derived DC populations in differential states of maturation. From a panel of known tumor-associated suppressive cytokines, IL-10 showed a unique ability to induce predominant migration of an immature CD14(+)CD141(+)DC-SIGN(+) DC subset with low levels of co-stimulatory molecules, up-regulated expression of the co-inhibitory molecule PD-L1 and the M2-associated macrophage marker CD163. A similarly immature subset composition was observed for DC migrating from explants taken from skin overlying breast tumors. Whereas predominant migration of mature CD1a(+) subsets was associated with release of IL-12p70, efficient Th cell expansion with a Th1 profile, and expansion of functional MART-1-specific CD8(+) T cells, migration of immature CD14(+) DDC was accompanied by increased release of IL-10, poor expansion of CD4(+) and CD8(+) T cells, and skewing of Th responses to favor coordinated FoxP3 and IL-10 expression and regulatory T cell differentiation and outgrowth. Thus, high levels of IL-10 impact the composition of skin-emigrated DC subsets and appear to favor migration of M2-like immature DC with functional qualities conducive to T cell tolerance.
    PLoS ONE 07/2013; 8(7):e70237. DOI:10.1371/journal.pone.0070237 · 3.23 Impact Factor
Show more