CD2 Distinguishes Two Subsets of Human Plasmacytoid Dendritic Cells with Distinct Phenotype and Functions

Matsui, Toshimichi; Connolly, John E.; Michnevitz, Mark; Chaussabel, Damien; Yu, Chun I.; Glaser, Casey; Tindle, Sasha; Pypaert, Marc; Freitas, Heidi; Piqueras, Bernard; Banchereau, Jacques; Palucka, A. Karolina

doi:10.4049/jimmunol.0802008

Cited by 174 publications

(180 citation statements)

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“…Surface expression of CD2 divides human pDCs into two distinct subsets. Whereas both CD2 lo and CD2 hi pDCs produce type I IFN, the CD2 hi subset secretes more IL12p40, triggers more T-cell proliferation (26), and is relatively resistant to apoptosis on the basis of higher BCL2 expression (28). Here we show that CD2 hi pDCs contain a unique subpopulation that expresses CD5 and CD81.…”

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confidence: 71%

“…Whether the diverse functions of pDCs are mediated by the same cells responding to different environmental cues or by distinct preprogrammed subsets or lineages is not clear, although several reports suggest the existence of phenotypically distinct subpopulations of pDCs in mice (23)(24)(25) and humans (26)(27)(28)(29)(30). Surface expression of CD2 divides human pDCs into two distinct subsets.…”

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confidence: 99%

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A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes

Zhang

Gregorio

Iwahori³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

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Plasmacytoid dendritic cells (pDCs) are known mainly for their secretion of type I IFN upon viral encounter. We describe a CD2 hi CD5 + CD81 + pDC subset, distinguished by prominent dendrites and a mature phenotype, in human blood, bone marrow, and tonsil, which can be generated from CD34 + progenitors. These CD2 hi CD5 + CD81 + cells express classical pDC markers, as well as the toll-like receptors that enable conventional pDCs to respond to viral infection. However, their gene expression profile is distinct, and they produce little or no type I IFN upon stimulation with CpG oligonucleotides, likely due to their diminished expression of IFN regulatory factor 7. A similar population of CD5 + CD81 + pDCs is present in mice and also does not produce type I IFN after CpG stimulation. In contrast to conventional CD5 − CD81 − pDCs, human CD5 + CD81 + pDCs are potent stimulators of B-cell activation and antibody production and strong inducers of T-cell proliferation and Treg formation. These findings reveal the presence of a discrete pDC population that does not produce type I IFN and yet mediates important immune functions previously attributed to all pDCs.P lasmacytoid dendritic cells (pDCs) are a distinct lineage of bone-marrow-derived cells that reside mainly in blood and lymphoid organs in the steady state, but can also be found in sites of infection, inflammation, and cancer (1). As one of the two principal lineages of dendritic cells, pDCs diverge from conventional DCs (cDCs) during maturation in the bone marrow and are recognized mainly for their rapid and massive production of type I IFN (IFNα/β) in response to viral infection (2). Although generally viewed as weak antigen-presenting cells by comparison with cDCs, pDCs interact with many types of cells, such as NK cells, cDCs, T cells, and B cells through their secretion of cytokines and chemokines in addition to type I IFN, as well as through their expression of various costimulatory molecules (3, 4). Thus, pDCs are capable of activating CD4 + helper and regulatory T cells and CD8 + cytotoxic T cells (5-16). They can also stimulate B-cell activation, differentiation into plasma cells, and antibody production through mechanisms that are not yet completely understood (17)(18)(19)(20)(21)(22).Whether the diverse functions of pDCs are mediated by the same cells responding to different environmental cues or by distinct preprogrammed subsets or lineages is not clear, although several reports suggest the existence of phenotypically distinct subpopulations of pDCs in mice (23-25) and humans (26-30). Surface expression of CD2 divides human pDCs into two distinct subsets. Whereas both CD2 lo and CD2 hi pDCs produce type I IFN, the CD2 hi subset secretes more IL12p40, triggers more T-cell proliferation (26), and is relatively resistant to apoptosis on the basis of higher BCL2 expression (28). Here we show that CD2 hi pDCs contain a unique subpopulation that expresses CD5 and CD81. Unlike CD2 hi CD5 − CD81 − pDCs, CD2 hi CD5 + CD81 + pDCs fail to produce type 1 IFN but ...

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mentioning

confidence: 71%

mentioning

confidence: 99%

A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes

Zhang

Gregorio

Iwahori³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

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“…Recently, it has been reported that gzmB is present in other leukocyte populations, namely, CD4 þ T cells, 33 B cells, 31 neutrophils, 29 basophils, 28 mast cells, 27 macrophages, 26 dendritic cells 32,52 and CD34 þ stem cells. 29,53 Although the function of gzmB produced by these cells is unknown, it seems to be granule associated.…”

Section: Serpinb9 and Granzyme Bmentioning

confidence: 99%

Control of granzymes by serpins

2009

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Although proteolysis mediated by granzymes has an important role in the immune response to infection or tumours, unrestrained granzyme activity may damage normal cells. In this review, we discuss the role of serpins within the immune system, as specific regulators of granzymes. The well-characterised human granzyme B-SERPINB9 interaction highlights the cytoprotective function that serpins have in safeguarding lymphocytes from granzymes that may leak from granules. We also discuss some of the pitfalls inherent in using rodent models of granzyme-serpin interactions and the ways in which our understanding of serpins can help resolve some of the current, contentious issues in granzyme biology. Cell Death and Differentiation (2010) 17, 586-595; doi:10.1038/cdd.2009; published online 6 November 2009As described elsewhere in this series, granzymes are key mediators of cytotoxic lymphocyte (CL) function, exhibiting both intracellular and extracellular functions. Thus, it is imperative that their activities be tightly controlled. Too little activity reduces the effectiveness of the immune system, resulting in infection and cancer. Conversely, overactivity can lead to disease caused by tissue destruction and cellular apoptosis. This review focusses on the manner in which granzyme activity is controlled at the posttranslational level by members of the serpin superfamily.The serpin superfamily is an ever-expanding group of structurally related proteins, currently comprising approximately 1000 members across all kingdoms of life. 1,2 Serpins function as intracellular or extracellular regulators of a wide range of physiological processes such as complement activation, blood coagulation and apoptosis. Within the vertebrate immune system, they control proteases of the classical and innate complement systems, and are also potent inhibitors of many leukocyte granule proteases. Serpin StructureStructures of almost 100 serpins from viruses to humans have been determined and all conform to the same basic architecture first described in 1984. The fold comprises nine a-helices, three b-sheets and a variable reactive centre loop (RCL), which is the primary site of interaction with target proteases (Figure 1a). The first structure determined was human SERPINA1 cleaved within the RCL. 3 Surprisingly, it was found that the residues around the cleavage point were separated by almost 70 Å , with the N-terminal portion of the RCL inserted into b-sheet A to form a fully antiparallel sixstranded sheet. It has subsequently been shown that, in the native state, the RCL is solvent exposed, and that its insertion into b-sheet A is a consequence of the inhibitory mechanism. The RCL is flanked by two highly conserved motifs (the proximal and distal hinges) that permit its insertion into b-sheet A. Insertion is also facilitated by the breach and shutter regions that assist the opening of b-sheet A and by the movement of helix F. 4 The RCL is a critical determinant of serpin inhibitory specificity, acting as a pseudosubstrate and cleavage site for the...

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“…Furthermore, pDCs can interact synergistically with myeloid DCs by enhancing their priming ability in a contact-dependent manner, resulting in increased levels of Ag-specific CTLs (3,10). Finally, activated pDCs abrogate cancer cell replication and induce tumor cell death (11).…”

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confidence: 99%

Human Plasmacytoid Dendritic Cells Phagocytose, Process, and Present Exogenous Particulate Antigen

Tel

Lambeck

Cruz

et al. 2010

The Journal of Immunology

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CD2 Distinguishes Two Subsets of Human Plasmacytoid Dendritic Cells with Distinct Phenotype and Functions

Abstract: high pDCs secrete higher levels of IL12p40, express higher levels of costimulatory molecule CD80, and are more efficient in triggering proliferation of naive allogeneic T cells. Thus, human blood pDCs are composed of subsets with specific phenotype and functions.

Cited by 174 publications

References 78 publications

A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes

A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes

Control of granzymes by serpins

Human Plasmacytoid Dendritic Cells Phagocytose, Process, and Present Exogenous Particulate Antigen

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