Human plasmacytoid dendritic cells efficiently cross-present exogenous Ags to CD8+ T cells despite lower Ag uptake than myeloid dendritic cell subsets

Abstract

Key Points• Cross-presentation of both soluble and cell-associated tumor antigens by human DC subsets is enhanced by addition of adjuvant TLR agonists. • Ability to cross-present exogenous antigen with high IFN␣ secretion puts human pDCs as activators of CD8 ϩ T cells in antitumor responses. IntroductionDendritic cells (DCs) are the professional antigen presenting cells (APCs) of the immune system with the unique capacity to attract and activate naive CD4 ϩ and CD8 ϩ T cells. 1 After infection or inflammation, DCs undergo a complex maturation process and migrate into lymph nodes where they present antigens (Ags) to T cells. The DC family is very heterogeneous and consists of different DC subsets, each with distinct functional characteristics. In human peripheral blood, at least 2 main populations of DCs can be distinguished: CD11c positive myeloid DCs (mDCs) and CD11c negative plasmacytoid DCs (pDCs). Myeloid DCs can be further subdivided based on the expression of CD16, CD1c, and BDCA3. 2 Transcriptional profiling revealed significant differences between the human blood DC subsets, 3 probably reflecting differences in their Ag-presenting capacities. Furthermore, mDCs and pDCs show clearly different responses to products derived from pathogens, as a result of their distinct Toll-like receptor (TLR) expression profiles. 4 Myeloid DCs have the capacity to produce IL-12 in response to microbial stimuli through TLRs, and thereby, induce Th1 responses. 5,6 Plasmacytoid DCs (pDCs), in contrast, are the key effectors in innate immunity because of their capacity to produce large amounts of type I IFNs in response to bacterial or viral infections. 7 Similar to mDC-derived IL-12, pDC-derived type I IFNs also participate in T-cell priming as Th1-inducing cytokines. 8 In addition to directing CD4 ϩ Th responses, DCs are also important for the generation of CD8 ϩ cytotoxic T-cell responses against viruses and tumors. As professional APCs, DCs have the unique capacity to take up, process, and present exogenously encountered Ags for cross-presentation via MHC class I molecules to CD8 ϩ T cells. Numerous studies have been performed to comprehend this cross-presentation process, and these have revealed 2 major pathways: (1) the "canonical" proteasome dependent cytosolic pathway, and (2) the TAP and proteasome independent pathway. [9][10][11][12] Many studies however, made use of murine DCs to study cross-presentation capacities and mechanisms used by different DC subsets. There is ample evidence that identified the CD8␣ ϩ DC as the superior cross-presenting DC subset in mice. 13,14 Recently, a lot of effort has been put toward finding the human counterpart of the murine cross-presenting CD8␣ ϩ DC subset. Despite basic similarities between human and mouse DCs, direct comparison is difficult because of large differences in cell-surface markers and TLR expression, in particular also for pDCs, which in contrast to mice are the sole TLR9-expressing subtype of DCs in Submitted June 7, 2012; accepted November 9, 2012. Prepublished onl...

Targeting Uptake Receptors on Human Plasmacytoid Dendritic Cells Triggers Antigen Cross-Presentation and Robust Type I IFN Secretion

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Effective Clinical Responses in Metastatic Melanoma Patients after Vaccination with Primary Myeloid Dendritic Cells

“…In vitro studies have already demonstrated that human mDCs and pDCs synergize via bidirectional cross-talk (11,42). Addition of CD141 þ myeloid DCs may even further improve the potency of DC vaccines, as CD141 þ DCs are highly efficient in antigen cross-presentation to CD8 þ T cells and are able to secrete IFNg and IL12 upon activation, which allows the effective induction of T helper 1 and CTL responses (43)(44)(45)(46)(47)(48). However, the limited presence of DCs in blood and lack of GMPgrade isolation reagents currently impedes the use of CD141…”

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

“…On pDCs, CD40 ligation has been described to augment the production of IL-6, thereby facilitating generation of antibody producing plasma cells (Jego et al, 2003). Furthermore, CD40 signaling can aid effective activation of T cells or prevent T cell exhaustion (Krug et al, 2001;Fonteneau et al, 2003;Tel et al, 2013;Fuse et al, 2009;Isogawa et al, 2013). In CHB patients low and exhausted T cells are consistently observed and held responsible for the inability to clear HBV (Ferrari et al, 1990;Jung et al, 1991;Boni et al, 2007Boni et al, , 2012Bertoletti and Ferrari, 2016).…”