# Regulation of human IL12/IL23 responsiveness by IL12RB1

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $379,920

## Abstract

ABSTRACT
Tuberculosis (TB) is a human disease caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb). In
2015, TB ranked above HIV/AIDs as a leading cause of death worldwide. The gene IL12RB1 regulates human
resistance to TB by promoting cytokine (IL12/IL23)-dependent differentiation of naïve TH cells into TH1 and
TH17 effectors. TH1 and TH17 cells limit Mtb survival by activating Mtb-infected macrophages and recruiting
neutrophils to infected sites. It was established >20 years ago that IL12RB1 is transcribed and translated into
IL12Rβ1, a transmembrane receptor on the TH cell surface that binds IL12/IL23, and then complexes with
secondary receptors (IL12Rβ2, IL23R) to activate the intracellular signaling cascades that drive TH1/TH17
differentiation. However, we recently demonstrated that IL12RB1 is also transcribed and translated into a
second isoform (Isoform 2, or Iso2) that is a secreted potentiator of IL12/IL23 activity. The mechanism whereby
Iso2 potentiates IL12/IL23 activity is not known. Here, we propose a research project that will both fill important
gaps in our knowledge of IL12RB1 and determine the mechanism of Iso2 potentiation. This project is
significant since IL12RB1 regulates multiple immune responses including TB-resistance, and innovative
since it will establish a paradigm for how natural soluble cytokine receptors potentiate cytokine activity. This
project is also being pursued by an investigator with demonstrated independent expertise and productivity in
the field of IL12RB1-TB interactions, in an environment that is highly supportive of basic immunology
research. Finally, the methods and approach we use build on our demonstrated expertise in molecular
biology, immunology and the mouse TB model. There are two Specific Aims: (AIM 1) Determine the
biochemical mechanism that Isoform 2 enhances IL12/IL23 signaling; (AIM 2) Determine the immunological
mechanism that Isoform 2 increases TB resistance. At the end of our studies, we will have extended our basic
understanding of IL12RB1 immunobiology in the context of TB, as well as generated novel proteins with
potential use as an adjunct TB therapy. Since IL12RB1's influence extends beyond TB to also include
autoimmunity, cancer, and atopic disease, the mechanisms we identify are relevant to these other human
diseases.

## Key facts

- **NIH application ID:** 9925176
- **Project number:** 5R01AI121212-05
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Richard Robinson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $379,920
- **Award type:** 5
- **Project period:** 2016-05-25 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925176

## Citation

> US National Institutes of Health, RePORTER application 9925176, Regulation of human IL12/IL23 responsiveness by IL12RB1 (5R01AI121212-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9925176. Licensed CC0.

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