Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses

Abstract

The SNP (c.1142G > A;p.R381Q) in the IL-23 receptor (IL23R) confers protection from multiple inflammatory diseases, representing one of the most significant human genetic polymorphisms in autoimmunity. We, therefore, sought to define the functional consequences of this clinically significant variant. We find that CD4+CD45RO+ and CD8+ T cells from healthy R381Q IL23R carriers show decreased IL-23-dependent IL-17 and IL-22 production relative to WT IL23R individuals. This was associated with a lower percentage of circulating Th17 and Tc17 cells. Furthermore, CD8+ T cells from R381Q IL23R individuals showed decreased IL-23-dependent expansion and signal transducer and activator of transcription 3 (STAT3) activation compared with WT CD8+ T cells. Importantly, cells transfected with the IL23R glutamine variant show decreased IL-23-mediated signaling compared with the IL23R arginine allele. Our results show that the R381Q IL23R variant leads to selective, potentially desirable, loss of function alterations in primary human CD4+ and CD8+ T cells, resulting in highly significant protection against autoimmunity.cytokines | Crohn's disease | ulcerative colitis | psoriasis T he IL-23/Th17 pathway is critical for optimal microbial defenses (1, 2); however, disregulation of this pathway can lead to inflammation (3-9). The SNP (c.1142G > A; p.R381Q) in IL-23 receptor (IL23R) confers protection from inflammatory diseases, including ankylosing spondylitis, psoriasis, and inflammatory bowel disease (10-12); it represents one of the most significant human genetic polymorphisms in autoimmunity. On binding to the IL23R complex, IL-23 mediates its effects by signaling through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and NF-κB pathways (13,14). IL-23 modulates responses in multiple cell populations, including differentiation and maintenance of CD4+ Th17 (6, 15-17) and CD8+ Tc17 cells (18)(19)(20)(21).We considered that the disease-protective R381Q IL23R may result in a loss of function, leading to decreased IL-23/Th17 pathway cytokine production, or a gain of function, leading to enhanced microbial clearance. We find that CD4+CD45RO+ and CD8+ T cells from healthy R381Q IL23R carriers show decreased IL-23-dependent IL-17 and IL-22 production relative to WT IL23R individuals. This was associated with a lower percent of circulating Th17 and Tc17 cells. Furthermore, R381Q CD8+ T cells showed decreased IL-23-and STAT3-dependent expansion and STAT3 activation compared with WT cells. Our results indicate that the protective R381Q IL23R variant leads to selective loss of function in primary human CD4+ and CD8+ T cells. ResultsMemory CD4+ T Cells from R381Q IL23R Individuals Show Decreased IL-23-Mediated Th17 Cytokine Production on in Vitro Stimulation. To define the role of the disease-protective R381Q IL23R polymorphism, we genotyped 650 healthy individuals and identified 48 individuals carrying the minor glutamine allele, consistent with prior estimates of a 7% allele frequency (11). WT individuals are...

Protective role of R381Q (rs11209026) polymorphism in IL-23R gene in immune-mediated diseases: A comprehensive review

“…suggested that IL-23R RQ381 exerted its protective effects by attenuation of IL-23-induced T H 17 functions (IL-17A production) without interfering with T H 17 differentiation (Pidasheva et al 2011). Further, Sarin et al (2011) showed that CD4 + CD45RO…”

“…Several mechanisms might contribute to these observations, including a reduced capacity of IL-23RQ381 to activate STAT proteins due to an impaired association of JAK2 proteins with the cytoplasmic tail of the receptor. As a result, R381Q CD8 + and T H 17 CD4 + T-cells displayed decreased IL-23-and STAT3-dependent expansion, STAT3 phosphorylation and STAT3 activation compared with WT cells (Sarin et al 2011) (Figure 6). …”

IL12/IL23 Inhibition in the Treatment of Psoriatic Arthritis

“…Initial clues to the involvement of the IL23/IL17 axis in spondyloarthritis (SpA) arose from the observation that a polymorphism in the receptor for IL23 (IL-23R) was associated with altered susceptibility to ankylosing spondylitis and PsA [17,18]. Specifically, R381Q IL23R carriers show decreased IL23-dependent IL17 and IL22 production and a lower percentage of circulating Th17 cells [19]. These individuals also showed a decreased IL23-dependent signaling.…”

Association between lower frequency of R381Q variant (rs11209026) in IL-23 receptor gene and increased risk of recurrent spontaneous abortion (RSA)

“…IL-23 has been linked with T H 17 cell responses, mainly through its effects on the expansion and maintenance of these cells (Peng et al, 2010;Sheibanie et al, 2007). IL-23 is also involved in the differentiation and maintenance of CD4 + T H 17 and CD8 + T C 17 cells (Sarin et al, 2011). This concept builds on the fact that serum levels of IL-17 (secreted by T H 17 cells) and IL-23 (inducer of inflammatory responses mediated by T H 17 cells) were significantly higher in patients with unexplained RSA than in controls (Pongcharoen et al, 2007).…”

“…The pro-inflammatory features of IL-23 have been linked with T H 17 cell responses through the expansion and maintenance of T H 17 cells (Gyulveszi et al, 2009;Guan et al, 2012;Hedrick et al, 2009;Peng et al, 2010;Sheibanie et al, 2007). IL-23 is also involved in the differentiation and maintenance of CD4 + T H 17 and CD8 + T C 17 cells (Sarin et al, 2011). As such, IL-23 has been recognized as a central cytokine in autoimmunity and a highly promising target for treatment in inflammatory diseases, including potentially RSA.…”