Dendritic cells (DCs) play critical roles in activating innate immune cells and initiating adaptive immune responses. subsets. eTOC Durai et al review the progress made in developing new mouse models for the analysis of the functions of dendritic cell subsets and what these models have revealed about the roles of these cells in immune responses Introduction The Sanggenone C vertebrate immune system has evolved the remarkable capacity to robustly and precisely eliminate the wide variety of potential threats it encounters, from single cell bacteria to multicellular parasites to even transformed oncogenic versions of its own cellular components. To achieve this goal, many diverse lineages of effector cells must act together in different capacities throughout the course of the immune response. As with any system possessing such complexity, the careful control and coordination of the numerous components of the immune system is critical for its proper functioning. As our understanding of each cell type acting within this system has grown, it has become increasingly apparent that dendritic cells (DCs) act as the central regulators of the entire immune response, responsible both for sensing the nature of the threats faced and for activating the precise combination of BTLA effectors required to eradicate them. First isolated by Ralph Steinman and Zanvil Cohn, DCs were identified by their stellate morphology and capacity to stimulate na?ve T cells (Steinman and Cohn, 1973; Steinman and Witmer, 1978; Nussenzweig et al., 1980). DCs comprise two major branches, the classical DCs (cDCs) identified by Steinman and the lymphocyte-like plasmacytoid DCs (pDCs) that produce Type 1 interferon in response to pathogens (Perussia et al., 1985; Heath and Carbone, 2009; Cella et al., 1999; Siegal et al., 1999). cDCs can be further divided into two major subsets recently renamed cDC1s and cDC2s (Guilliams et al., 2014). All DCs originate from bone marrow (BM) progenitors arising from hematopoietic stem cells, starting with the macrophage/dendritic cell progenitor (MDP) (Fogg et al., 2006; Auffray et al., 2009), which gives rise to the common dendritic cell progenitor (CDP) (Naik et al., 2007; Onai et al., 2007), which finally gives rise to committed progenitors for each Sanggenone C branch of DC such as the pre-cDC1 and the pre-cDC2 (Grajales-Reyes et al., 2015; Schlitzer et al., 2015). cDCs express the integrin CD11c and MHC class II (Steinman et al., 1979; Metlay et al., 1990), and each subset can be distinguished by additional markers. Resident cDC1s in the spleen and lymph nodes (LNs) express CD8, CD24, and XCR1, while cDC2s express CD4 and Sirp (Mildner and Jung, 2014; Murphy et al., 2016). In nonlymphoid tissues, all cDCs express CD24, which distinguishes them from macrophages that instead express CD64 (Schlitzer et al., 2013; Plantinga et al., 2013; Langlet et al., 2012). Nonlymphoid tissue cDC1s also express XCR1 and CD103, while cDC2s express CD11b and Sirp. Migratory cDCs that traffic from nonlymphoid tissues to LNs express these same markers they expressed in the periphery. There are several exceptions to these rules, however, such as CD11b+ cDC2s in the small intestine that comprise both CD103+ and CD103? fractions (Bogunovic et al., 2009; Satpathy et al., 2013). While these varied markers have historically been used to identify cDC subsets, a recent analysis suggests that a more simple and consistent identification of these cells across most tissues is possible by gating cDCs as CD11c+MHCII+CD26+CD64?F4/80?, and within this population cDC1s as XCR1+ and cDC2s as Sirp+ (Guilliams et al., 2016). Sanggenone C pDCs also express CD11c and MHCII, but can be segregated by their additional expression of B220, Siglec-H, and Bst2 (Blasius et al., 2006; Zhang et al., 2006). While cDCs were discovered for their ability to serve as potent antigen-presenting cells (APCs), it is now clear that they also have nonredundant roles in innate immune responses (Mashayekhi et al., 2011; Satpathy et al., 2013). Their early recognition of pathogens and rapid cytokine production activates innate immune cells such as innate lymphoid cells Sanggenone C (ILCs) and natural killer (NK) cells to limit pathogen spread until adaptive immunity can be initiated. Indeed, the heterogeneity of cDCs can itself be.