Differential regulation of naïve and memory CD4+ T cells by alternatively activated dendritic cells

Abstract

Promising immunotherapeutic tools for T cell-mediated pathologies are alternatively activated dendritic cells (aaDC), which exert their effect through the regulation and tolerization of T cells. As naïve and memory T cells have different susceptibilities to tolerogenic signals, it is important to understand the modulatory effects of aaDC on these T cell subsets. We have examined regulation of naïve and memory CD4+ T cells by human aaDC generated with dexamethasone, the active form of vitamin D3, 1α,25-dihydroxyvitamin D3, and LPS. Although aaDC induced low, primary, allogeneic responses by naïve and memory T cells, aaDC regulated the differentiation of these T cell subsets in a distinct manner. Naïve T cells primed by aaDC retained a strong, proliferative capacity upon restimulation but were skewed toward a low IFN-γ/high IL-10 cytokine profile. In contrast, memory T cells primed by aaDC became hyporesponsive in terms of proliferation and cytokine production. Induction of anergy in memory T cells by aaDC was not a result of the presence of CD25hi regulatory T cells and could be partially reversed by IL-2. Both T cell subsets acquired regulatory activity and inhibited primary CD4 and CD8 responses. Addition of exogenous IL-12p70 during T cell priming by aaDC prevented anergy induction in memory T cells and cytokine polarization in naïve T cells, indicating that the lack of IL-12p70 is a key feature of aaDC. Our finding that aaDC differentially regulate naïve and memory T cells is important for understanding and maximizing the therapeutic potential of aaDC.

Therapeutic effect of tolerogenic dendritic cells in established collagen‐induced arthritis is associated with a reduction in Th17 responses

“…Previously, our group demonstrated that human dexamethasone/vitamin D 3 -treated tolerogenic DCs polarize naive T cells toward high IL-10 production in vitro (25). Here, we show for the first time that tolerogenic DCs can promote IL-10-producing T cells in vivo in the setting of inflammation, such as that associated with severe arthritis.…”

“…Treatment of DCs with 1␣,25-dihydroxyvitamin D 3 (vitamin D 3 ) in combination with dexamethasone has been shown to synergistically inhibit lipopolysaccharide (LPS)-induced maturation of DCs (24). Previously, we used these immunosuppressive drugs to generate human tolerogenic DCs with potent immunoregulatory function in vitro (25,26). An important outstanding question is, however, whether these pharmacologically modified tolerogenic DCs can inhibit pathogenic IL-17-mediated responses in vivo, and whether they will be effective at reducing the progression and severity of arthritis when administered after disease onset.…”

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

“…Immunoregulatory molecules and markers, including PD-L1, PD-L2, B7-H3, B7-H4, CD103 and ILT3/4, increased production of immunoregulatory cytokines and factors (e.g., IL-10, IL-1β, TGF-β, indoleamine 2,3-dioxygenase (IDO), arginase I, iNOS) or decreased production of pro-inflammatory cytokines (e.g., IL-6, IL-12, IL-15, TNF-α, IL-1α) have been described in different regDC model systems [1,[20][21][22][23][24][25]. Plasmacytoid regDCs might express CCR9 [26]; in cancer, plasmacytoid regDCs may be identified as cells expressing FOXO3 [27].…”

Role of innate immunity in tolerance induction

“…В настоящее время активно исследуется влияние различных иммуносупрессивных лекарств на дифференцировку ДК и их функцию [118]. Среди наиболее часто используемых лекарств для генерации толерогенных ДК в лабораторных условиях -дексаметазон, уже упоминавшийся витамин D 3 (1a,25(ОН) 2 D 3 и его аналоги), а также рапамицин [64,65,[119][120][121][122][123][124][125]. Все эти лекарства имеют общее свойство -они индуцируют дифференцировку фенотипически зрелых ДК, которые имеют низкую стимулирующую способность Т-клеток и не становятся иммуностимуляторами в ответ на сигналы зрелости ДК.…”

“…Недавно предложенная стратегия доставки биодеградируемых микрочастиц, выделяющих рапамицин, зрелым ДК [128], может быть использована для ДК-специфичной доставки и других иммуномодулирующих препаратов. Комбинация дексаметазона и витамина D 3 также использовалась для индукции толерогенных ДК [65,124,125,129,130]. Преимущество комбинирования этих стероидов в том, что они значительно ингибируют созревание и функцию ДК аддитивным образом [126].…”