# Mechanisms of IL-6 mediated T cell pathogenesis in autoimmunity

> **NIH NIH R01** · BENAROYA RESEARCH INST AT VIRGINIA MASON · 2020 · $841,259

## Abstract

PROJECT ABSTRACT
The IL-6 signaling pathway is dysregulated in autoimmunity in part through increased expression of the
membrane bound IL-6R (mbIL-6R). The central hypothesis for the proposed studies is that elevated mbIL-6R
expression leads to altered T cell fate and function resulting in pathogenic autoreactive T cells due to changes
in the magnitude and balance of STAT1 and STAT3 phosphorylation. The following three Specific Aims will
address this hypothesis. Aim 1 studies will determine the regulation of mbIL-6R expression in T cells from type
1 diabetes (T1D), relapsing remitting multiple sclerosis (RRMS) and rheumatoid arthritis (RA) subjects at the
genetic, transcriptional, translational and post-translation level, focusing on the contribution of the
IL6RAsp358Ala variant and ADAM17 mediated shedding. Aim 2 studies will determine how increased mbIL-6R
alters the magnitude and balance of STAT1 and STAT3 phosphorylation and how these changes influence the
T cell response with respect to lineage commitment, homing and response to regulation. These studies will
take advantage of a cohort of healthy subjects with genetically determined mbIL-6R expression levels. Aim 3
studies will determine the impact of elevated mbIL-6R expression on both total T cells and autoreactive T cells
in T1D, RRMS and RA. The primary endpoints will be T cell lineage commitment, transcriptional profile, and
response to regulation. This aim will also determine the effect of elevated mbIL-6R expression on the islet
specific T cell response to tocilizumab in T1D. The studies proposed in this application are appropriate for the
“High Priority Immunology Grant (R01)” mechanism as it is research investigating the immunological
mechanisms of autoimmune disease pathogenesis using well-defined human cohorts, high resolution
immunophenotyping and systems immunology. These studies will advance our understanding of how subtle
alterations in IL-6 signaling, contribute to the development and potentiation of autoimmunity.

## Key facts

- **NIH application ID:** 9968002
- **Project number:** 5R01AI132774-04
- **Recipient organization:** BENAROYA RESEARCH INST AT VIRGINIA MASON
- **Principal Investigator:** Jane Hoyt Buckner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $841,259
- **Award type:** 5
- **Project period:** 2017-07-18 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968002

## Citation

> US National Institutes of Health, RePORTER application 9968002, Mechanisms of IL-6 mediated T cell pathogenesis in autoimmunity (5R01AI132774-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9968002. Licensed CC0.

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