Plasmacytoid Dendritic Cells and Immunotherapy in Multiple Sclerosis

Felipe von Glehn; Leonilda M Santos; Konstantin E Balashov

Disclosures

Immunotherapy. 2012;4(10):1053-1061. 

In This Article

Characterization of pDCs

pDCs are known to be a small population of bone marrow-derived cells (0.3–0.5% of the human peripheral blood) that traffic directly from blood via high endothelial venules to organized lymphoid structures in the steady state, mainly to T-cell areas of lymph nodes and spleen, mucosal-associated lymphoid tissues, thymus and liver.[3,14,15] They originate in the bone marrow from a common dendritic cell (DC) progenitor, a distinct progenitor type that expresses cytokine receptors Flt3, M-CSFR (CD115) and low levels of c-Kit (CD117).[16,17] The cytokine Flt3 ligand appears to provide the central signal for pDC development, through its receptor and transcription factor STAT3, controlling the expansion of common progenitors and peripheral DC homeostasis.[18] The pDC lineage commitment is linked to expression of the basic helix-loop-helix transcription factor E2-2 (E protein), which controls the synthesis of other pDC-specific transcription factors involved in cell development and function, for example, BDCA-2, ILT-7 and IRF7.[19] The low expression of the DNA-binding protein inhibitor ID-2, in contrast to abundant ID-2 expression in T, NK and myeloid cells, increases the effective E2-2 concentration in pDCs.[19]

Immature pDCs express low levels of MHC class II and costimulatory molecules. pDCs are negative for the integrin CD11c but positive for the B-cell marker B220/CD45RA.[20] Furthermore, they have been found to contain recombination-activating gene products and show D–J rearrangements of the immunoglobulin heavy chains.[21] Notably, these features of steady-state pDCs are similar to those of lymphocytes but are distinct from those of conventional DCs (cDCs).

pDCs can be distinguished from other blood cells based on the selective expression of BDCA-2[6,7] and ILT-7.[22,23] Human pDCs also express CD4, MHC class II, IL3R, BDCA-4 (neuropilin-1) and CD2.[24] Human pDCs lack the lineage markers CD3, CD19, CD14, CD16 and cDC marker CD11c.[24]

Although most nucleated cells produce type I IFN-α/β) upon infection with viruses, pDCs have the unique feature of producing more type I interferons than any other cell type in response to viruses and/or virus-derived nucleic acids.[25] TLR7 and 9 are highly expressed in pDCs and B cells. Upon activation with viral nucleic acids, they induce stimulation and recruitment of the adaptor protein MyD88 and two major TLR7/9 intracellular signaling pathways. The first pathway leads to type I interferon production, which requires the translocation of IRF7 to the nucleus promoting IFN-α/β transcription[26,27] and the second pathway leads to expression of TNF-α and IL-6, mediated by NF-κβ signaling.[28] TLR7 and 9 are exclusively expressed in intracellular endosomal compartments.[29] TLR7 recognizes viral ssRNA[30,31] and TLR9 detects viral dsDNA rich in unmethylated CpG oligonucleotides.[32,33] This leads to induction of type I interferon secretion in an IFN-α/β receptor-independent manner,[34] although this IFN-α/β receptor-mediated positive feedback is still active in pDCs.[35]

To avoid the possibility of uncontrolled interferon secretion, multiple pDC-specific molecules inhibit human pDC function. BDCA-2 and ILT-7 attenuate Toll-like receptor (TLR)-induced production of interferons and other cytokines.[36] They signal through a common pathway that involves the γ- and α-chain of the high-affinity Fc receptor for IgE (FcεRIγ and FcεRIα)[22] and NKp44, which signals through DAP12.[37]

Furthermore, when activated, pDCs produce IL-6, TNF-α and chemokines, for example, CXCL9 (MIG), CXCL10 (IP-10), CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES),[38] which are able to attract activated CD4 and CD8 T cells to the sites of inflammation and upregulate the chemokine receptor CCR7, directing them through its ligand CCL21 and CCL19 to secondary lymph organs to prime naive T cells.[39] Recent data obtained in situ showed that pDCs accumulate in lesions of type I interferon-related disorders (e.g., lupus erythematosus and psoriasis), Th2 cell-dominated allergic reactions and ovarian carcinoma.[40] This migratory pathway to peripheral nonlymphoid tissues is poorly understood. Human pDCs express ChemR23, which directs pDC migration through its agonist chemerin.[41] Chemerin is constitutively produced by endothelial cells and fibroblasts as an inactive chemokine precursor and activated by serine proteases produced in damaged tissues.[41] Additional chemoattractants for pDCs in damaged tissues are adenosine[42] and anaphylatoxins C3a and C5a.[43] pDCs also express CXCR3, a receptor for the inflammatory chemokines CXCL10 (IP-10), CXCL11 (ITAC) and CXCL9 (MIG), as well as CXCR4, a receptor for CXCL12 (SDF-1). CXCR4–SDF-1 interactions are an important mechanism of extravasation of pDCs to lymphoid tissues.[38] Therefore, pDCs may influence both innate and adaptive immune responses.

Type I interferons, secreted by pDCs activated with foreign nucleic acids, promotes long-term T-cell survival and memory,[44,45] Th1 polarization,[46] CD8 T-cell cytolytic activity, NK cell-mediated cytotoxicity and IFN-γ production.[47,48] On the other hand, in the presence of only IL-3 and CD40 ligand, pDCs undergo a different maturation process[3] and, in vitro, induce naive T cells to produce Th2 cytokines.[49]

IL-6 and type I interferons can induce the differentiation of B cells into immunoglobulin-producing plasma cells.[50,51] However, it seems that a physical interaction between pDC CD70, a TNF family ligand expressed after CpG-oligodeoxyribonucleotide activation, and CD27 expressed on memory B cells, is a stronger differentiation promoter, indicating the role of pDCs in B-cell growth and differentiation.[52,53]

In addition to abundant cytokine production, TLR-mediated activation leads to pDC maturation associated with upregulation of costimulatory molecules (CD40, CD80, CD86 and CD137L), increased expression of MHC class II and capability to stimulate T cells.[54] This process is specifically mediated by NF-κβ signaling.[28] Activated pDCs can efficiently present antigens and prime and cross-prime T lymphocytes.[55] Different from cDCs, which have the ability to accumulate long-lived MHC class II–peptide complexes for a short period after activation, pDCs maintain the capacity to present antigens after activation, which is important when they become infected with viruses. The pDCs continuously display the repertoire of exogenous and endogenous antigens contained in the surrounding environment.[55] Recent studies demonstrated that pDCs could convert to cDCs after culture with certain stimuli (e.g, IL-3, CD40L, viruses or TLR ligands),[13] probably related to reduced transcription factor protein E2-2 expression.[19] This differentiation would automatically terminate high-level type I interferon secretion, shorten the lifespan of infected pDCs and facilitate T-cell priming to viral antigens.[20]

The tolerogenic property of pDCs has been associated with the expression of the intracellular enzyme indoleamine 2,3-dioxygenase (IDO). IDO is rarely expressed by lymphoid cells under physiologic conditions. Its expression is tightly regulated and is responsive to inflammatory signals such as type I and II interferons.[28] Activated under certain conditions, pDCs may express IDO.[55] IDO catabolizes tryptophan, consumes reactive oxygen species[56] and generates metabolites known as kynurenines.[57] Its immunosuppressive effect may be linked to the reduction of local tryptophan concentration and kynurenine metabolites affecting activated T cells.[58] Furthermore, pDCs expressing IDO reduce their ability to stimulate clonal expansion of effector T cells, enhance their ability to suppress T-cell responses[28,59,60] and promote generation of Tregs.[58]

In addition, human pDCs constitutively express high levels of ICOS-L,[61] which promotes survival, expansion and IL-10 production of a subset of FoxP3+ Tregs expressing ICOS.[62]

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