Kathleen F. Nolan
IL-10-Conditioned Dendritic Cells, Decommissioned for Recruitment of Adaptive Immunity, Elicit Innate Inflammatory Gene Products in Response to Danger Signals
Nolan, Kathleen F.; Murray, John; Strong, Victoria; Soler, Dulce; Nurse, Beth; Fairchild, Paul J.; Cobbold, Stephen P.; Croxton, Ruth; Gonzalo, Jose-Angel; Rubio, Ana; Wells, Meghan; Waldmann, Herman
Professor John Murray John.Murray@hull.ac.uk
Professor of Robotics and Autonomous Systems
Paul J. Fairchild
Stephen P. Cobbold
Dr Ruth Croxton R.Croxton@hull.ac.uk
Dendritic cells (DCs) are the professional APCs of the immune system, enabling T cells to perceive and respond appropriately to potentially dangerous microbes, while also being able to maintain T cell tolerance toward self. In part, such tolerance can be determined by IL-10 released from certain types of regulatory T cells. IL-10 has previously been shown to render DCs unable to activate T cells and it has been assumed that this process represents a general block in maturation. Using serial analysis of gene expression, we show that IL-10 pretreatment of murine bone marrow-derived DCs alone causes significant changes in gene expression. Furthermore, these cells retain the ability to respond to Toll-like receptor agonists, but in a manner skewed toward the selective induction of mediators known to enhance local inflammation and innate immunity, among which we highlight a novel CXCR2 ligand, DC inflammatory protein-1. These data suggest that, while the presence of a protolerogenic and purportedly anti-inflammatory agent such as IL-10 precludes DCs from acquiring their potential as initiators of adaptive immunity, their ability to act as initiators of innate immunity in response to Toll-like receptor signaling is enhanced.
Dendritic cells (DCs)3 are not only recognized as important initiators of immunity, characteristically unique in their ability to stimulate naive T cells, but also as key determinants of the type of immunity initiated. They have variously been termed “sensors of infection” and “plastic”, reflecting their ability to convey context of Ag encounter to direct adaptive immunity (1, 2), while “immature” DCs have been implicated in mediating peripheral tolerance (3, 4). Under experimental conditions, a number of agents have been reported to modulate the immunostimulatory potential of DCs (3, 5). Modulation by IL-10 results in DCs that are no longer capable of presenting Ag for immunity, but induce Ag-specific anergy in both CD4+ and CD8+ T cells (5, 6, 7, 8).
Classic maturation of DCs in response to inflammatory stimuli involves extensive reprogramming, manifest as a temporally coordinated cascade, facilitating the conversion of cells specialized for high Ag uptake, but exhibiting poor T cell stimulatory properties, to cells that no longer sample Ag, but are highly efficient T cell stimulators (2, 9). This conversion is accompanied by changes in migration priorities, initially facilitating recruitment and then release of DCs from the site of inflammation, and subsequently homing of Ag-bearing mature DCs to lymphoid tissue. Inflammatory mediators produced early in the response at the site of activation are replaced at later time-points by mediators promoting DC:T cell interactions (10). IL-10 does not effect the capacity of immature DCs for Ag uptake, but does prevent the chemokine receptor switch required for maturation-induced lymphoid homing, and alters Ag presentation, preventing up-regulation of MHC class II, as well as costimulatory and adhesion molecules, impeding acquisition of T cell stimulatory capacity (5, 7, 11, 12). Given these observations, it has been suggested that IL-10 mediates its immunosuppressive effects on DCs by blocking normal maturation (7, 11). An alternative proposal is that DCs are actively “conditioned” by IL-10 to modify the quality of any subsequent response to stimuli (13).
In this study, we have used serial analysis of gene expression (SAGE) (14) to identify genes regulated following LPS-induced maturation of murine bone marrow-derived DCs (BMDCs), and to investigate changes in this regulation effected by pretreating the cells with IL-10. This analysis has facilitated the identification and cloning of a novel LPS-induced chemokine, the functional characteristics and induction of which are consistent with activity during the early proinflammatory phase of DC maturation. Pretreatment with IL-10 did not hinder the induction of this, or other related chemokines. SAGE library comparisons indicate that IL-10 conditions BMDCs to acquire a state from which, although compromised in their ability to present Ag for immunity, they remain competent to generate innate immune responses to microbial danger signals.
|Journal Article Type||Article|
|Start Date||Jul 3, 2017|
|Publication Date||Feb 15, 2004|
|Journal||Journal of Immunology|
|Publisher||American Association of Immunologists|
|Peer Reviewed||Peer Reviewed|
|APA6 Citation||Nolan, K. F., Croxton, R., Strong, V., Soler, D., Fairchild, P. J., Cobbold, S. P., …Waldmann, H. (2004). IL-10-Conditioned Dendritic Cells, Decommissioned for Recruitment of Adaptive Immunity, Elicit Innate Inflammatory Gene Products in Response to Danger Signals. Journal of Immunology, 172(4), 2201-2209. https://doi.org/10.4049/jimmunol.172.4.2201|
|Related Public URLs||https://ora.ox.ac.uk/objects/uuid:807f7a57-fcdc-450a-a48a-ea2d36f7a8a1|
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