IL12Rβ1: The cytokine receptor that we used to know

Abstract

Human IL12RB1 encodes IL12Rβ1, a type I transmembrane receptor that is an essential component of the IL12- and IL23-signaling complex. IL12RB1 is well-established as being a promoter of delayed type hypersensitivity (DTH), the immunological reaction that limits tuberculosis. However, recent data demonstrate that in addition to promoting DTH, IL12RB1 also promotes autoimmunity. The contradictory roles of IL12RB1 in human health raises the question, what are the factors governing IL12RB1 function in a given individual, and how is inter-individual variability inIL12RB1 function introduced? Here we review recent data that demonstrate individual variability in IL12RB1 function is introduced at the epigenetic, genomic polymorphism, and mRNA splicing levels. Where and how these differences contribute to disease susceptibility and outcome are also reviewed. Collectively, recent data support a model whereinIL12RB1 sequence variability – whether introduced at the genomic or post-transcriptional level - contributes to disease, and that human IL12RB1 is not as simple agene as we once believed.

A Variety of Alu-Mediated Copy Number Variations Can Underlie IL-12Rβ1 Deficiency

“…The human IL12RB1 gene is located on chromosome 19p13 and has 17 exons. IL12RB1 encodes the β1 chain common to the receptors for IL-12 and IL-23 [20, 21]. To date, 213 patients from 164 kindreds worldwide have been reported to have complete IL-12Rβ1 deficiency [1–19] and many more have probably been diagnosed.…”

The introduction of RNA-DNA differences underlies interindividual variation in the human IL12RB1 mRNA repertoire

“…Consistent with this role, IL12RB1 polymorphisms produce IL12Rβ1 proteins of varying sensitivity to IL12/23 (5) and associate with susceptibility to numerous diseases regulated by IL12/23, including tuberculosis, nontuberculous mycobacterial infection, malaria, cancer, pediatric asthma, and atopic dermatitis (4). Here we report that in addition to containing genome-encoded polymorphisms, IL12RB1 mRNA transcripts expressed in peripheral blood mononuclear cells (PBMCs) and inflamed lungs also contain multiple RNA-DNA differences (RDDs) that concentrate in sequences encoding the IL12Rβ1 cytokine-binding region.…”

“…Interleukin-12 receptor β1 (IL12RB1) encodes IL12Rβ1, a type 1 transmembrane protein that positively regulates human IL12/23 sensitivity by binding the IL12p40-domain common to both cytokines (4). Consistent with this role, IL12RB1 polymorphisms produce IL12Rβ1 proteins of varying sensitivity to IL12/23 (5) and associate with susceptibility to numerous diseases regulated by IL12/23, including tuberculosis, nontuberculous mycobacterial infection, malaria, cancer, pediatric asthma, and atopic dermatitis (4).…”

Insights into IL-23 biology: From structure to function

“…Like IL-12 also IL-12Rβ1 was initially isolated from human tissue. The discovery of IL-12 initiated studies to identify the receptor which is responsible for the bioactivity of the cytokine [44]. For the cloning of the human IL-12 receptor a non-neutralizing anti-human IL-12R antibody (2-4E6), which immunoprecipitates the complex formed between IL-12 and IL-12 binding protein(s), was used to screen a cDNA library derived from PBMCs of healthy donors activated with PHA (phytohemagglutinin) [23].…”