cDCs comprise two major subsets, cDC1s and cDC2s. Both sub sets express CD11c and MHC class II molecules. In humans, cDC1s are characterized by the expression of CD141 (BDCA-3), CLEC9A, XCR1 and CADM1, whereas cDC2s express CD1c (BDCA-1), SIRPα (CD172), and CD11b. In mice, cDC1s also express XCR1, CLEC9A, CADM1, as well as CD8a/CD103 and cDC2s express SIRPα, CD4, and CD11b. Although these markers define the cDC1 subset quite precisely, cDC2 markers are less specific and do not address the heterogeneity within the cDC2 subset. Recent studies by independent groups have identified that the classically defined cDC2 subset comprise multiple subpopulations, which are detailed in the “New Developments in DC Classification” section.
The development of cDC subsets is regulated by distinct transcriptional programs. cDC1s express interferon regulatory factor (IRF) 8, basic leucine zipper transcriptional factor ATF-like 3 (Batf3), and DNA-binding protein inhibitor 2 (ID2). cDC2s express IRF4 and Kruppel-like factor 4 (Klf4). Notch signaling also plays an essential role in the development and differentiation of cDCs. Evidence for the importance of Notch signaling in DC programming comes from in vitro cultures both in murine and human systems, in which DCs are generated in the presence of OP9 cells, a stromal cell line supporting the differentiation of HSCs. Specifically, in the context of human cells, expanding cord blood or peripheral blood CD34+ precursor cells with key factors for DC growth and differentiation, namely Flt3-L, SCF, IL-7, and thrombopoietin (TPO) and subsequently inducing their differentiation in the presence of OP9 feeder cells, generated primarily pDCs with small frequencies of cDCs. In the same system, when Notch ligand DLL1 expressing OP9-DLL1 cells were used as feeders, pDC generation was suppressed and the proportion of cDCs, particularly cDC1s, were greatly increased, which transcriptionally, phenotypically, and functionally resembled their primary blood cDC1 counterparts. Other studies in murine models have also demonstrated nonredundant roles for Notch signaling in cDC2 differentiation and function, particularly in T follicular helper (TFH ) cell differentiation and induction of B cell responses during infection.
Both cDC subsets are known for their unique efficacy for priming naïve T cells and inducing their functional polarization. Additionally, cDC1s, expressing an array of immunoregulatory molecules, are key for tolerogenic regulation. cDC1s are superior to cDC2s at antigen cross-presentation, a process through which exogenous antigens are acquired and presented on MHC class I molecules, thereby inducing CD8+ T cell responses. While cDC1s can also activate CD4+ T cells and polarize them toward a Th1 phenotype, cDC2s are the main subset specialized in MHC class II-mediated antigen presentation. cDC2s efficiently activate CD4+ T cells and induce their polarization toward Th1, Th2, and Th17 phenotypes in specific contexts. cDC2 is the most frequent DC population and found in blood, lymphoid, and non-lymphoid tissues, while cDC1s are thought to primarily reside in the lymph nodes (LNs) and found in trace numbers in the blood. Another distinct feature between cDC1 and cDC2 subsets is the differential expression of pattern recognition receptors (PPRs), which recognize conserved molecules displayed by pathogens or damaged cells. cDC1s express Toll-like receptors (TLRs) 3 and 8. Due to TLR3 triggering, cDC1s have the unique ability to produce type III interferons, which contribute to antiviral and antitumor immunity. cDC2s express a wide range of PRRs, TLRs 1–8, and produce IL-23, a critical cytokine for innate defense. Hence, cDC2s mediate antimicrobial responses against a greater variety of pathogens.
