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

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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.

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We would like to thank and acknowledge the following individuals, whose work contributed to indicated Figures: Jill Waukau and Christine Bengtson (Figs. 1 and 2), Mark McNally and Lisa McNally (Figs. 4 and 5), Katrina Monson and Brady Brooks (Fig. 6). We would also like to thank Abigail Robinson for the chromosome 19 karyotype image in Fig. 7. This work was supported by the Medical College of Wisconsin (MCW) and National Institutes of Health grant R01 AI121212 (to RTR).

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Correspondence to Richard T. Robinson.

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Reeme, A.E., Claeys, T.A., Aggarwal, P. et al. Human IL12RB1 expression is allele-biased and produces a novel IL12 response regulator. Genes Immun 20, 181–197 (2019) doi:10.1038/s41435-018-0023-2

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