The Dichotomous Pattern of IL-12R and IL-23R Expression Elucidates the Role of IL-12 and IL-23 in Inflammation

Abstract

IL-12 and IL-23 cytokines respectively drive Th1 and Th17 type responses. Yet, little is known regarding the biology of these receptors. As the IL-12 and IL-23 receptors share a common subunit, it has been assumed that these receptors are co-expressed. Surprisingly, we find that the expression of each of these receptors is restricted to specific cell types, in both mouse and human. Indeed, although IL-12Rβ2 is expressed by NK cells and a subset of γδ T cells, the expression of IL-23R is restricted to specific T cell subsets, a small number of B cells and innate lymphoid cells. By exploiting an IL-12- and IL-23-dependent mouse model of innate inflammation, we demonstrate an intricate interplay between IL-12Rβ2 NK cells and IL-23R innate lymphoid cells with respectively dominant roles in the regulation of systemic versus local inflammatory responses. Together, these findings support an unforeseen lineage-specific dichotomy in the in vivo role of both the IL-12 and IL-23 pathways in pathological inflammatory states, which may allow more accurate dissection of the roles of these receptors in chronic inflammatory diseases in humans.

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

“…The activation of NK cells by CD1c + DCs is driven by IL-12p70, leading to CD69 upregulation as well as IFN-γ (Gerosa et al, 2005, Perrot et al, 2010. These findings are further supported by a recent report that human NK cells express high levels of IL12Rβ1 and IL-12Rβ2, which encodes for IL-12R (Chognard et al, 2014). However, CD1c + DCs may not be reactivating pathogenic Th17.1 responses given the lack of GM-CSF induction from memory CD4 + T cells, as well as being equivalent to monocytes at reactivating 125 | P a g e memory CD4 + T cells to produce IL-6, IL-17A, IL-21 and IL-22.…”

“…This was most likely due to the difference in antibody sources (i.e the one used in our study was a monoclonal IgG vs polyclonal goat IgG used by Wilson et al). (Chognard et al, 2014). NK cells in our 116 | P a g e study were identified as CD3 -CD56 + CD161 + , whereby CD161 is a marker of NK cells (Lanier et al, 1994) and we observed IL-23R staining on a small percentage of NK cells.…”

“…Consistent with this finding, our study confirmed that human γδ T cells represent the major IL-23R + expressing cells. In humans, numerous methods have been adopted to identify IL-23R expression including the use of a fluorescent IL-23R antibody (Kenna et al, 2012), fluorescent polyclonal IgG antibody (Wilson et al, 2007) or PCR (Billerbeck et al, 2010, Chognard et al, 2014, Rachitskaya et al, 2008, Shen et al, 2013. Using these strategies, human γδ T cells, memory CD4 + and CD8 + T cells have been reported to express IL-23R (Kenna et al, 2012, Oppmann et al, 2000, Shen et al, 2013, Wilson et al, 2007.…”

“…In our study, the IL-23R expression on Th17 and Th17.1 cells was characterised using expression may be limited to a small proportion of Th cells, which may be a preventative measure against prolonged or enhanced inflammatory response which could lead to harmful effects on the host. Furthermore, the contribution of IL-23/IL-23R towards disease pathology has been highly characterised in human tissues, including the skin and gut (Capon et al, 2007, Cargill et al, 2007, Chognard et al, 2014, McGovern et al, 2009, Silverberg et al, 2009, Zwiers et al, 2012.…”

“…NK cells lack the CD3 marker but express CD56 and CD161 (Lanier et al, 1994, Pampena andLevy, 2015). NK cells are known to respond towards IL-12p70 given its high expression of IL-12Rβ1 and IL-12Rβ2, leading to the induction of IFN-γ (Chognard et al, 2014, Fauriat et al, 2010, Gerosa et al, 2005. Gerosa et al…”