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

Gaëlle Chognard,Adam-Nicolas Pelletier,Nicolas Morin,Sylvie Lesage,Guy Charron,Durga Sivanesan,Lisa Bellemare,Claudine Beauchamp,Ramnik Xavier,Maria C Dominguez-Punaro,Sylvain Chemtob,Vijay Kuchroo,Stephen W Michnick,John D Rioux,Marie-Josée Guyon,Christina Bursill

doi:10.1371/journal.pone.0089092

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.

Highlights

The heterodimeric receptors for both IL-12 and IL-23 share a common protein subunit, namely IL-12Rb1, and are often depicted at the same cell membrane [1,2,3,4,5]
IL23R and IL12RB2 are not Transcribed within the Same Lymphocyte Populations. As both IL-12 and IL-23 receptors share a common subunit, namely IL-12Rb1, it has been implied that these receptors are coexpressed
IL23R mRNA expression was limited to T cell subsets, with highest expression in both CD8 and cd T cells, while IL12RB2 mRNA was expressed in both cd T cells and NK cells (Figure 1A)

Summary

Introduction

The heterodimeric receptors for both IL-12 and IL-23 share a common protein subunit, namely IL-12Rb1, and are often depicted at the same cell membrane [1,2,3,4,5]. IL-12Rb2 and IL-23R, the respective specific subunits of IL-12 and IL-23 receptors, show high homology and likely arose by gene duplication [1]. A recent GWA study of primary biliary cirrhosis revealed an association with IL12RB2, IL12A (a gene encoding for the p35 subunit of the IL-12 cytokines) and STAT4 (downstream of IL12RB2) [9,15]. Genetic polymorphisms in both the IL-12 and IL-23 pathways are strongly associated with susceptibility to inflammatory diseases. It is imperative that we understand the cellular players of the IL-12 and IL-23 pathways and their role in inflammation

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Conclusion