Human plasmacytoid dendritic cells are unresponsive to bacterial stimulation and require a novel type of cooperation with myeloid dendritic cells for maturation

Abstract

Dendritic cell (DC) populations play unique and essential roles in the detection of pathogens, but information on how different DC types work together is limited. In this study, 2 major DC populations of human blood, myeloid (mDCs) and plasmacytoid (pDCs), were cultured alone or together in the presence of pathogens or their products. We show that pDCs do not respond to whole bacteria when cultured alone, but mature in the presence of mDCs. Using purified stimuli, we dissect this cross-talk and demonstrate that mDCs and pDCs activate each other in response to specific induction of only one of the cell types. When stimuli for one or both populations are limited, they synergize to reach optimal activation. The cross-talk is limited to enhanced antigen presentation by the nonresponsive population with no detectable changes in the quantity and range of cytokines produced. We propose that each population can be a follower or leader in immune responses against pathogen infections, depending on their ability to respond to infectious agents. In addition, our results indicate that pDCs play a secondary role to induce immunity against human bacterial infections, which has implications for more efficient targeting of DC populations with improved vaccines and therapeutics. IntroductionDendritic cells (DCs) are arrayed with diverse pathogen sensors (eg, Toll-like receptors (TLR)) and reside in tissues throughout the body, rendering them uniquely poised to detect invading pathogens. 1,2 During the initiation and amplification of the immune response, DCs rally other cells of both the innate and adaptive immune systems for the elimination of infections. 3,4 In the context of different infections, DC populations are also critical in determining the quality of the response through the efficient and rapid production of discrete subsets of cytokines, chemokines, and interferons (IFNs), which selectively direct the recruitment and activation of other immune effectors. 3,4 Because DCs are key antigen-presenting cells (APCs), the instructive role of DC soluble factors shapes adaptive immunity in various ways, resulting in focused and optimized antigen-specific responses to different pathogen classes (eg, viruses vs bacteria). 5,6 There are numerous distinct DC populations that vary in their tissue distribution, cytokine/chemokine secretion, and/or their interactions with infectious agents and other cells of the host. [7][8][9][10] Of these, blood myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) represent 2 well-characterized populations that differ in their morphology, phenotype, TLR expression, and cytokine, chemokine, and type I IFN production. [10][11][12][13][14] These differences imply that mDCs and pDCs have evolved to sense distinct classes of pathogens and selectively steer subsequent innate and adaptive immunity. Even though both DC types are considered effective APCs, 11,15 the nonoverlapping distribution of TLRs and the pattern of cytokine production in human mDCs and pDCs suggest specialized and perhaps complementary functi...

Human Plasmacytoid Dendritic Cells Phagocytose, Process, and Present Exogenous Particulate Antigen

“…First,the composition of the studied particulates(apoptotic cells, beads, bacteria, or PLGA microparticles) is diverse and uptake might require different receptors and uptake mechanisms, some of which may not be exploited by pDCs. Furthermore, some studies compared the phagocytic capacity of pDCs to that of moDCs and found that pDCs showed very little to no uptake compared with moDCs (3,14,18). We also found that moDCs were superior to pDCs in phagocytosing particulate Ag, notwithstanding that almost all pDCs engulfed particles.…”

“…In this study, we investigated whether pDCs can play a role in immune responses against exogenous particulates. Up to now, it was highly controversial whether pDCs are able to respond to stimuli entrapped in particle-like structures (3,8,9,14,(16)(17)(18)(19). We demonstrate that pDCs are clearly capable of phagocytosing Ag entrapped within PLGA microparticles and subsequent processing of the encapsulated Ag.…”

“…Human pDCs have been shown to prime functional T cell responses on phagocytosis of apoptotic debris (16). However, Piccioli and coworkers (3) postulate that pDCs cannot phagocytose bacteria (Staphylococcus aureus and Escherichia coli) and require myeloid DCs to respond to bacterial stimuli. On the contrary, other studies show that pDCs can be activated by extracellular bacteria (S. aureus and Streptococcus pyogenes), but it was not established whether this was due to uptake of entire bacteria or mere bacterial components (8,9).…”

“…Recently, it was shown that not only viruses, but also whole live bacteria can induce pDC activation, resulting in Th1 polarization of naive CD4 + T cells (8,9). Furthermore, pDCs can interact synergistically with myeloid DCs by enhancing their priming ability in a contact-dependent manner, resulting in increased levels of Ag-specific CTLs (3,10). Finally, activated pDCs abrogate cancer cell replication and induce tumor cell death (11).…”

“…pDCs differ from myeloid DCs in their ability to produce large amounts of type I IFNs (IFN-a and IFN-b), thereby providing an immunostimulatory environment for both innate and adaptive immune cells. Type I IFNs are known to be important for antiviral immunity, but several studies show that they also play a role in bacterial infections and cancer immunity (3,4). Although unstimulated pDCs promote an unbiased Th or a Th2 response, activated pDCs promote DC activation and trigger a Th1 response (5-7).…”