Costimulatory Molecules on Immunogenic Versus Tolerogenic Human Dendritic Cells

Abstract

Dendritic cells (DC) are sentinels of immunity, essential for homeostasis of T cell-dependent immune responses. Both functions of DC, initiation of antigen-specific T cell immunity and maintenance of tissue-specific tolerance originate from distinct stages of differentiation, immunogenic versus tolerogenic. Dependent on local micro milieu and inflammatory stimuli, tissue resident immature DC with functional plasticity differentiate into tolerogenic or immunogenic DC with stable phenotypes. They efficiently link innate and adaptive immunity and are ideally positioned to modify T cell-mediated immune responses. Since the T cell stimulatory properties of DC are significantly influenced by their expression of signal II ligands, it is critical to understand the impact of distinct costimulatory pathways on DC function. This review gives an overview of functional different human DC subsets with unique profiles of costimulatory molecules and outlines how different costimulatory pathways together with the immunosuppressive cytokine IL-10 bias immunogenic versus tolerogenic DC functions. Furthermore, we exemplarily describe protocols for the generation of two well-defined monocyte-derived DC subsets for their clinical use, immunogenic versus tolerogenic.

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

“…Expression of surface molecules associated with DC maturation like CD83, the lymph node homing receptor CCR7 and MHC class-II molecules is reduced on IL-10-induced regDCs. In contrast, expression of inhibitory receptors such as immunoregulatory receptors like ILT2, ILT3, and ILT4 are increased on IL-10-induced regDCs, which has been suggested to be involved in tolerance induction [53]. The amount of proinflammatory cytokines released by IL-10-induced regDCs, like IL-6 and TNF-α, is similar to classically matured DCs.…”

“…In contrast, IL-10 production is dramatically increased suggesting another possible mechanism resulting in tolerance induction [54][55][56]. Several studies showed that in vitro generated tolerogenic IL-10-DCs have an even higher capacity to induce iTreg than tissue resident immature DCs [53]. Thus, a reduced expression of immunostimulatory molecules combined with a higher expression of inhibitory costimulators and the production of IL-10 may facilitate tolerogenic functions of IL-10-induced regDCs.…”

“…In addition, IL-10 DC-primed anergic CD4 + and CD8 + T cells exhibit suppressive capacity and are able to inhibit activated Th1, Th2, and Tc1 T cell responses [29]. Compared to tolerogenic tissue resident DCs, IL-10-induced regDCs are terminally differentiated and exhibit a stable phenotype [53] and have been confirmed in peripheral blood of humans [55].…”

“…IL-10/IL-10R-signaling is mediated by activation of the Jak/STAT pathway through tyrosine phosphorylation of Tyk2/Jak1, resulting in downstream activation and homodimerization of STAT3. In the context of DC maturation by several stimuli the most important pathways affected by IL-10 are PI3K/Akt/NF-κ B-, MyD88/MAPK-, and Ras/Raf/MAPK-regulated signal transduction cascades [53]. Maturation of DC in the presence of IL-10 induces two distinct subsets of tolerogenic DCs characterized in humans as CD83 high CD80/CD86 high HLA-DR high and as CD83 low CD80/CD86 low HLA-DR low .…”

Importance of Feedback and Feedforward Loops to Adaptive Immune Response Modeling

“…The fate of T cells is determined by the strength and kinetics of different costimulatory and co‐inhibitory molecules. Most studied co‐inhibitory molecules include CTLA‐4, programmed cell death protein 1 (PD‐1), and B‐ and T‐lymphocyte attenuator (BTLA) 40, 41…”