Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells

Abstract

The cellular sources of interleukin-6 (IL-6) that are relevant for the differentiation of TH17 cells remain unclear. Here, we used a novel strategy of IL-6 conditional deletion of distinct IL-6-producing cell types to show that Sirpα+ dendritic cells (DC) were essential for the generation of pathogenic TH17 cells. During the process of cognate interaction, Sirpα+ DCs trans-presented IL-6 to T cells using their own IL-6Rα. While ambient IL-6 was sufficient to suppress the induction of the transcription factor Foxp3 in T cells, IL-6 trans-presentation by DC-bound IL-6Rα (here defined as IL-6 cluster signaling) was required to prevent premature induction of IFN-γ in T cells and to generate pathogenic TH17 cells in vivo. These findings will guide therapeutic approaches for TH17-mediated autoimmune diseases.

Human IL-6R hi TIGIT − CD4 + CD127 low CD25 + T cells display potent in vitro suppressive capacity and a distinct Th17 profile

“…Furthermore, IL-6 signalling is increased in T1D patients owing to increased IL-6R expression [41]. These results indicate that inhibition of IL-6 signalling could be a therapeutic approach in T1D, as it is in other human inflammatory diseases [42], [43]. Nevertheless, blockade of IL-6, which is a key pathway in immune defence, could raise the risk of serious infections in T1D patients and hence targeting the therapy to a specific cell type could offer advantages in therapy.…”

Genetic ablation of histone deacetylase 2 leads to lung cellular senescence and lymphoid follicle formation in COPD/emphysema

“…Based on the strategic localization of BALT structures, we assume that the production of proinflammatory cytokines by epithelial cells can create the ideal conditions for triggering formation of ectopic LFs. For example, IL-6, in combination with TGF, is critical in inducing the differentiation of T helper 17 cells (63,64). Interestingly, IL-17 induces the expression of neutrophil-attracting chemokine KC by epithelial cells (65).…”

Effects of interleukin‐6 receptor blockade on allergen‐induced airway responses in mild asthmatics

“…Because gp130 is ubiquitously expressed, IL‐6 trans‐signalling widens the range of cell types that respond to IL‐6. A third IL‐6 signalling mode was described recently, termed IL‐6 cluster signalling, which involves presentation of mIL‐6R‐bound IL‐6 by dendritic cells to gp130‐expressing T cells …”

“…A third IL-6 signalling mode was described recently, termed IL-6 cluster signalling, which involves presentation of mIL-6R-bound IL-6 by dendritic cells to gp130expressing T cells. 17 Numerous studies have suggested a role for IL-6 signalling in asthma pathophysiology, some of these reviewed previously. [18][19][20] In clinical studies, IL-6 levels have been reported to be elevated in asthmatics, both systemically and in the airways.…”

“…Most of these pro-inflammatory effects of IL-6 have been suggested to be mediated by the trans-signalling pathway. [38][39][40][41] Exceptions include, for example, the generation of pathogenic Th17 cells 17,33 and mucus production, 8 which appear to be dependent on IL-6 cluster and/or classic signalling. Although broadly pro-inflammatory, IL-6 can also mediate anti-inflammatory effects, including inhibition of dendritic cell maturation 42,43 ; control of bacterial infections, 44 likely mediated by classic signalling 45 ; and mucosal protection from, or repair after, epithelial damage, [46][47][48][49] likely though trans-signalling.…”