The role of dendritic cells in systemic lupus erythematosus

Following the discovery of dendritic cells (DCs) in mice by Ralph Steinman in 1973, the early nineties saw the description of different culture conditions, allowing the generation of large numbers of DC, and energized the study of DCs in both health and disease. Because DCs are the primary line of defense against pathogens that invade the body, they form a critical interface between innate and adaptive immunity. Under steady state conditions, DCs play important roles in the establishment of central and peripheral tolerance. Their critical role in maintaining a balance between immunity and tolerance led to the hypothesis that their uncontrolled activation might drive autoimmune diseases including systemic lupus erythematosus (SLE).

Dendritic cell origins, subsets, and functions

Origins

DCs generally have a short half-life of 3–6 days and are constantly repopulated from hematopoietic stem cells (HSCs) residing in the bone marrow. HSCs differentiate into macrophage and DC progenitors (MDPs), which do not constitute a homogeneous population but rather consists in a mixture of progenitors committed either to the DC lineage or the monocyte/macrophage lineage when they are transferred into the bone marrow of hosts that have previously been irradiated. MDPs express M-CSF-R (or CD115) and the Flt3 receptor (CD135), which are receptors for cytokines that play important roles in the development of monocytes or DCs, respectively. It is likely that the commitment shift of MDPs into monocytes or common dendritic cells progenitors (hCDPs) depends on the balance between signals linked to the activation of these receptors. The hCDPs on the one hand generate pDCs, and on the other hand generate pre-cDCs, which are the direct circulating precursors of the cDCs in tissues. In parallel, the generation of cDC1 and cDC2 by hCDP occurs by production of a circulating progenitor, namely the hPre-cDC, which is incapable of generating pDCs.

Subsets/functions

A novel classification of DCs has emerged primarily based on their ontogeny replacing the previous one that was associated to their location, function, and phenotype. This divides DCs and related myeloid lineages into conventional or myeloid DCs (cDCs), plasmacytoid DCs (pDCs), and monocyte-derived cells (Mo-DCs).

Conventional/myeloid DCs

In humans, cDCs are highly specialized in antigen processing and presentation; they are present in the circulation and in lymphoid and non-lymphoid tissues. There is a general consensus that there are two populations of cDCs, namely cDC1 and cDC2, which are endowed with distinct functional specialization and thus play complementary roles in the shaping of immune responses. The two subpopulations can be distinguished based on surface markers: cDC1 (BDCA3 ⁺ CD141 ⁺ Clec9 ⁺ XCR1 ⁺ CD14 ⁻ CD16 ⁻ ) cDC2 (BDCA1 ⁺ CD1c ⁺ CD11b ⁺ CD1a ⁺ CD14 ⁻ CD16 ⁻ ). cDC2 secrete elevated amounts of inflammatory such as TNFa and IL12 and are essential in the presentation of exogenous antigens to CD4 T cell, while cDC1 are specialized in the cross-presentation of exogenous antigen in the context of MHC-I to CD8 T cells. Recent evidence also supports a role for cDC1 in the production of type III interferons in response to viral infections. cDCs are present in multiple tissues in an immature state under steady state conditions. Their maturation is induced by the recognition of Pathogen Associated Molecular Patterns (PAMPs) and Danger Associated Molecular Patterns (DAMPs) through Pattern Recognition Receptors (PRR) with. Such recognition activates multiple signaling cascades, which triggers DC production of inflammatory cytokines, optimize antigen-presentation capacity (by upregulating class I and II histocompatibility complex and co-stimulatory molecules at their surface) and facilitates DC homing to lymphoid tissues via afferent lymph vessels. In lymphoid tissues cDCs present antigen to naïve T cells, inducing an antigen specific immune response. Depending on infectious and environmental factors sensed in the periphery, mature cDCs polarize naive T cells into Th1, Th2, Th17, Tfh, or Treg cells through the secretion of distinct cytokines. As an example, cDC1 are characterized by the expression of TLR3 that is required for sensing of viral RNA, and by a greater capacity for secretion of the cytokine IL-12p70 following their activation, and Th1 polarization. In contrast, the development and maintenance of cDC2 appear to be dependent on the IRF4 transcription factor and the activation of Notch-2 receptors. This population of cDCs appears to be more efficient than the cDC1 in terms of the interaction with CD4 ⁺ T lymphocyte and the polarization of helper T lymphocytes, particularly for Th2 and Th17, which are implicated in immune responses toward extracellular pathogens and the regulation of immunity.

Plasmacytoid DCs

pDCs are found in blood, as well as in peripheral lymphoid and non-lymphoid tissues. pDCs can be distinguished from cDCs by a round morphology and by the expression of the surface markers CD123(IL3-R), CD303 (BDCA2), and CD304 (BDCA4). At the steady state, pDCs are poor antigen-presenting cells for naive T cells, but they are robust producers of type I IFN, rendering them very important in the defense against viral infections. Accordingly, within 6 hours of viral activation, most of the transcriptome of human pDCs is composed of type I IFN transcripts, and within 24 hours they secrete up to 1000-fold more IFN-α than any other blood cell type, a direct consequence of their constitutive IRF7 expression. pDCs preferentially express intracellular Toll-like receptors, including TLR7 and TLR9, that can respectively recognize ssRNA and ssDNA, and transduce signals on sensing viral and self-nucleic acids.

Monocyte-derived DCs (Mo-DCs)

Mo-DCs only detected under inflammation have been initially described in mice and then in humans. They are CD11c ⁺ HLA ^— DR ⁺⁺ CD16 ^— and exhibit molecular features of both cDCs and inflammatory macrophages. They express transcriptional factors implicated in DC differentiation, such as ZBTB46. Gene set enrichment analysis showed that Mo-DCs are specifically enriched in the monocyte-derived DC gene signature and are therefore most likely derived from monocytes rather than from DC precursors. They perform several functions in the tissues, such as antigen presentation to effector T cells, pathogen clearance and cytokine production. It has been shown that culturing allogeneic naive CD4 ⁺ T cells with Mo-DCs gived rise to Th1, Th2, or Th17 cells.

DCs and tolerance

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