Natural killer (NK) cells and dendritic cells (DCs) are two distinct cell types of innate immunity. It is known that the in vitro interaction of human NK cells with autologous DCs results in DC lysis. Here we show that contact-dependent interactions between activated human NK cells and immature DCs (iDCs) provides a “control switch” for the immune system. At low NK/DC ratios, this interaction dramatically amplifies DC responses, whereas at high ratios it completely turns off their responses. Specifically, culture of activated human NK cells with iDCs, at low NK/DC ratios (1:5), led to exponential increases in DC cytokine production, which were completely dependent on cell-to-cell contact. DC maturation was also driven by cognate interactions with NK cells and maturation was dependent on endogenously produced TNF-α in the culture. At slightly higher NK/DC ratios (5:1), inhibition of DC functions was the dominant feature due to potent killing by the autologous NK cells. Resting NK cells also stimulated autologous DC maturation in a TNF-α/contact-dependent manner, however, increasing the NK/DC ratio only led to an enhancement of this effect.

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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...

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