IL-1β Promotes the Differentiation of Polyfunctional Human CCR6+CXCR3+ Th1/17 Cells That Are Specific for Pathogenic and Commensal Microbes

Abstract

In humans, Th1/17 cells, identified by co-expression of the chemokine receptors CCR6 and CXCR3, have been proposed to be highly pathogenic in several autoimmune disorders due in part to their expression of the pro-inflammatory cytokines IL-17, IFN-γ and GM-CSF. However, their developmental requirements, relationship with “classic” Th17 and Th1 cells and physiological role in normal immune responses are not well understood. Here, we examined CCR6+CXCR3+ Th1/17 cells from healthy individuals, and found that ex vivo those cells produced the effector cytokines IL-17, IL-22 and IFN-γ in all possible combinations, and were highly responsive to both IL-12 and IL-23. Moreover, although the antigen specificity of CCR6+CXCR3+ Th1/17 cells showed substantial overlap with that of Th1 and Th17 cells, this population was enriched in cells recognizing certain extracellular bacteria and expressing the intestinal homing receptor integrin β7. Finally, we identified IL-1β as a key cytokine that renders Th17 cells sensitive to IL-12, and both cytokines together potently induced the differentiation of cells that produce IL-17, IFN-γ and GM-CSF. Therefore, interfering with IL-1β and IL-12 signaling in Th17 cells during inflammation may be a promising therapeutic approach to reduce their differentiation into “pathogenic” CCR6+CXCR3+ Th1/17 cells in patients with autoimmune diseases.

The role of human CD1c+ DCs at activating innate and adaptive immune responses

“…Interestingly, stimulation of Th17 cells with IFN-γ in combination with IL12p70 promotes up-regulation of IL-12Rβ2 expression (Lexberg et al, 2010). Similarly, the combined presence of IL-1β and IL-12p70 enhanced STAT4 and T-bet expression in Th17 cells (Duhen and Campbell, 2014). These findings, therefore suggest that the presence of both cytokines promote the transition of Th17 cells by conferring IL-12p70 responsiveness.…”

“…This was an important finding as Th17 cells themselves are able to produce TNF-α, which might be able to promote their transition towards Th1 phenotype either via the autocrine or paracrine mechanism. IL-1β and IL-12p70 can synergistically enhance the expression of T-bet as well as STAT4 expression in Th17 cells rendering them sensitive towards IL-12p70 stimulation, resulting in co-production of IFN-γ, IL-17A and GM-CSF (Duhen and Campbell, 2014). In mice, IL-23 has been suggested to promote autoimmunity partially due to its ability to induce IFN-γ, IL-17A and GM-CSF , El-Behi et al, 2011, Hirota et al, 2011.…”

“…In humans, high levels of GM-CSF have been documented in RA and multiple sclerosis (Noster et al, 2014, Reynolds et al, 2015. Duhen et al reported the synergy between IL-1β and IL-12p70 induced high levels GM-CSF from human Th17 cells (Duhen and Campbell, 2014). Furthermore, pathogenic Th17.1 cells isolated from gut inflamed tissues of CD patients express high levels of CSF2 mRNA which encodes for GM-CSF (Ramesh et al, 2014), indirectly suggesting a pathogenic role of GM-CSF in disease pathology.…”

“…Th17 cells are capable of transitioning towards a Th1 cell phenotype, and these cells are now referred to as Th17/1 or Th17.1 cells (Annunziato et al, 2007, Duhen and Campbell, 2014, Ramesh et al, 2014 Human DCs express extracellular and endosomal TLRs which are capable of detecting PAMPs and DAMPs. Upon recognition, DCs produce a wide array of cytokines and are able to polarise naïve CD4 + T cells to differentiate into specific Th subtypes.…”

CCR6-CCL20 Axis in IBD: What have we learnt in the past 20 years?

“…Those TH17 cells were of TH1/17 type and expressed the gut homing receptor, integrin β7 and receptors capable of recognizing extracellular bacteria. They concluded that this particular cell subset was specific for microbial induced pathogenesis [32].…”