Human IL12RB1 expression is allele-biased and produces a novel IL12 response regulator

Abstract

Human IL12RB1 is an autosomal gene that is essential for mycobacterial disease resistance and T cell differentiation. Using primary human tissue and PBMCs, we demonstrate that lung and T cell IL12RB1 expression is allele-biased, and the extent to which cells express one IL12RB1 allele is unaffected by activation. Furthermore, following its expression the IL12RB1 pre-mRNA is processed into either IL12RB1 Isoform 1 (IL12Rβ1, a positive regulator of IL12-responsiveness) or IL12RB1 Isoform 2 (a protein of heretofore unknown function). T cells’ choice to process pre-mRNA into Isoform 1 or Isoform 2 is controlled by intragenic competition of IL12RB1 exon 9-10 splicing with IL12RB1 exon 9b splicing, as well as an IL12RB1 exon 9b-associated polyadenylation site. Heterogeneous nuclear ribonucleoprotein H (hnRNP H) binds near the regulated polyadenylation site, but is not required for exon 9b polyadenylation. Finally, microRNA-mediated knockdown experiments demonstrated that IL12RB1 Isoform 2 promotes T cell IL12 responses. Collectively, our data support a model wherein tissue expression of human IL12RB1 is allele-biased and produces an hnRNP H bound pre-mRNA, the processing of which generates a novel IL12 response regulator.

Differential expression of an alternative splice variant of IL-12Rβ1 impacts early dissemination in the mouse and associates with disease outcome in both mouse and humans exposed to tuberculosis

“…IL-12Rβ1 exhibits a marked degree of variability at the genomic5, transcriptional 47 and splice variant level 17 suggesting that it is a highly flexible receptor with the capacity to both stimulate and inhibit cellular responses. Our observation that ΔTM-IL-12Rβ1 is secreted 15 suggests that it acts to sequester cytokine and regulate activation of cells however it appears to drive activation of T cells 8, 18 and is a positive regulator of immunity. Its effects in mouse lungs suggests that, just as for type 1 IFN 48 a little bit is good and required for optimal control of bacterial dissemination but too much completely limits dissemination and hampers induction and expression of protective immunity.…”

“…We knew from our previous studies that the ΔTM-IL-12Rβ1 message was induced early in the lungs of C57BL/6J (B6) mice exposed to low dose aerosol infection 8 . We also knew that the global inability to make the ΔTM-IL-12Rβ1 resulted in increased dissemination of bacteria to the periphery and reduced ability to generate IFN-γ producing T cells 15, 18 . We wanted to determine whether this observation was unique to the resistant B6 strain of mouse or if there was differential expression in mice which are substantially more susceptible to the low dose aerosol challenge 38 .…”

“…In contrast, total lack of the splice variant results in slightly higher dissemination of bacteria from the lung 15 and this effect can be seen if either myeloid or lymphoid cells lack the ΔTM-IL-12Rβ1. The increased effect of the absence of the ΔTM-IL-12Rβ1 in CD4 cells may reflect the role of the ΔTM-IL-12Rβ1 in augmenting IL-12p70-induced IFN-I production in T cells 15, 18 , while the impact of the loss of ΔTM-IL-12Rβ1 in the CD11c expressing cells may reflect the disruption of protective cytokine balance at the beginning of infection. The very early but short lived ΔTM-IL-12Rβ1 response of the human dendritic cells to live Mtb infection suggests that the signal is highly regulated and that sustained expression in myeloid cells may reflect ongoing exposure to live bacteria.…”

“…The ΔTM-IL-12Rβ1 locates to the endoplasmic reticulum 16 and can be secreted by transfected cells and mitogen-activated T cells blasts 15 . Human cells produce a similar splice variant of the IL12RB1 gene in response to Mtb exposure and this is referred to as isoform 2 8, 17 and has been shown to augment human T cell responsiveness to IL-12p70 18 . Our data supports the hypothesis that the alternative splice variant of IL-12Rβ1 plays an early role in initiation of T cell activation in response to aerosol infection with Mtb and that the production of this splice variant in human TB merits investigation.…”

Trichostatin A, a Histone Deacetylase Inhibitor, Alleviates Eosinophilic Meningitis Induced by Angiostrongylus cantonensis Infection in Mice

“…The expression profiles of Il12rb1 , Lrp10 , and Nfkbia were similar to that of NF-κB p65 . Il12rb1 promotes IFN-γ immunity, mycobacterial disease resistance, and T cell differentiation (Chua et al, 1995; Robinson et al, 2010; Bustamante et al, 2014; Reeme et al, 2019). The main function of Il12rb1 is cooperating with the proinflammatory cytokines interleukin-12 and interleukin-23 (IL12/23) to stimulate the signaling pathways.…”