Dendritic cells (DC) are key regulators of both protective immune responses and tolerance to self-antigens. Soon after their discovery in lymphoid tissues by Steinman and Cohn, as cells with the unique ability to prime naïve antigen-specific T cells, it was realized that DC can exist in at least two distinctive states characterized by morphological, phenotypic and functional changes-this led to the description of DC maturation. It is now well appreciated that there are several subsets of DC in both lymphoid and non-lymphoid tissues of mammals, and these cells show remarkable functional specialization and specificity in their roles in tolerance and immunity. This review will focus on the specific characteristics of DC subsets and how their functional specialization may be regulated by distinctive gene expression programs and signaling responses in both steady-state and in the context of inflammation. In particular, we will highlight the common and distinctive genes and signaling pathways that are associated with the functional maturation of DC subsets. Dendritic cell heterogeneityDendritic cells are cells of the mononuclear phagocyte system and develop in the bone marrow from common DC precursors that give rise to plasmacytoid DCs (pDCs) and to intermediate cells known as pre-conventional DC (pre-cDC). After exiting the bone marrow, precDC transiently circulate in the bloodstream and migrate into lymphoid and non-lymphoid tissues where they differentiate into cDC, pDC also enter tissues from the blood stream, constitutively in the case of secondary lymphoid organs but only upon inflammation in the case of non-lymphoid tissues. Analysis of secondary lymphoid organs (spleen, lymph nodes) and of non-lymphoid tissues (skin, intestine, lung, skeletal muscle and liver) has led to the identification of several distinct populations of cDC. Regardless of their anatomical location or species of origin, cDC can be grouped into two major subsets based on their phenotype, gene expression program, functional specialization and the transcription factors that specify their development (Guilliams et al, 2010) (Fig 1).Xcr1 + and CD11b + cDC The expression of CD8a or CD103 at the cell surface was originally used to classify a subset of cDC, often referred to as CD8a-type cDC. However, CD8a expression does not constitute a "universal" marker of this subset and CD103 is also expressed by intestinal cDC belonging to a second subset known as CD11b + cDC (see below). In contrast, the chemokine receptor Xcr1 has been recently shown to be strictly specific for CD8a-type cDC (Bachem et al, 2012;Crozat et al, 2011). The C-type lectin Clec9a (also known as Dngr1) is also selectively expressed on CD8a-type cDC, but also on pDC and on a subset of DC progenitors (Schraml et al, 2013). On that basis, CD8a-type cDC will be denoted as Xcr1 + cDC for the purpose of this review. The human DC subset often referred to as CD141 (BDCA3) + cDC, is the equivalent of mouse Xcr1 + cDC (Robbins et al, 2008; Haniffa et al, 2012) and can also be ide...
Dendritic cells (DCs) are instrumental in the initiation of T cell responses, but how thymic and peripheral tolerogenic DCs differ globally from Toll-like receptor (TLR)-induced immunogenic DCs remains unclear. Here, we show that thymic XCR1(+) DCs undergo a high rate of maturation, accompanied by profound gene-expression changes that are essential for central tolerance and also happen in germ-free mice. Those changes largely overlap those occurring during tolerogenic and, more unexpectedly, TLR-induced maturation of peripheral XCR1(+) DCs, arguing against the commonly held view that tolerogenic DCs undergo incomplete maturation. Interferon-stimulated gene (ISG) expression was among the few discriminators of immunogenic and tolerogenic XCR1(+) DCs. Tolerogenic XCR1(+) thymic DCs were, however, unique in expressing ISGs known to restrain virus replication. Therefore, a broad functional convergence characterizes tolerogenic and immunogenic XCR1(+) DC maturation in the thymus and periphery, maximizing antigen presentation and signal delivery to developing and to conventional and regulatory mature T cells.
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