# Innate mechanisms of regulation of Th17 responses

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $477,000

## Abstract

Project Summary/Abstract
Induction of inflammation by canonical microbial ligands by engaging classical patten recognition receptors
(PRR) has many beneficial outcomes including elimination of the pathogen and activation of adaptive
immunity that serves as protection against reinfection. However, unwarranted inflammation can also be
induced by aberrant activation of PRRs by noxious agents (toxins, uric acid etc) or because of naturally
occurring mutations in sensors or adapters of the innate immune system leading to auto-inflammatory
diseases such as Cryopyrin Associated Inflammatory Syndromes, and Interferonopathies. Auto-immune
diseases on the other hand are different than auto-inflammatory diseases as the culprits that trigger
pathology are self-reactive T and B cells. Auto-immune inflammation can lead to debilitating outcomes
because of damage to vital organs such as kidney, pancreas intestines as well as Skin and joints.
Paradoxically, many of the clinical treatments for T cell auto-immune diseases are all directed towards
inflammatory cytokines made by the innate immune system. Our previous work demonstrated that effector
and effector memory CD4 T cells have the capacity to drive IL-1b production, completely independent of
pattern recognition receptor activation. We discovered that Effector CD4 T cells provide both signal 1
(TNFa) and signal 2 (FasL) to instruct the myeloid cells to produce IL-1b in a Caspase-8 dependent
manner. The current proposal is based on very strong preliminary data that demonstrates that effector CD4
T cells in fact have the capacity to mimic microbial ligands to drive a broad pro-inflammatory program in
cells of the innate immune system. We find that effector memory CD4 T cells induce additional genes in
Dendritic cells that sets up important questions related to “T cell instruction” of the innate immune system.
Here we posit that while proximal activation of PRRs is necessary for naïve T cell activation, effector
memory T cells have the ability to directly activate the innate immune system thus bypassing the need for
PRR sensing. Although this might have evolved as a beneficial arm of the innate adaptive cross-talk, we
propose to understand the detrimental outcomes of adaptive instruction of innate immunity in driving
inflammation and tissue pathology. In order to gain mechanistic understanding of innate inflammation driven
by effector CD4 T cells, we propose three aims where 1. We will examine and characterize the nature of
innate inflammation driven by different effector memory T cell lineages and identify the molecular players
involved in this process, 2. We will investigate the molecular mechanisms by which effector memory CD4 T
cells drive innate inflammation with a particular focus on STING and DNA damage and 3. We will examine
the impact of CD4 T cell effector/effector memory CD4 T cell driven innate inflammation on auto-immune
disease and pathology. Successful completion of these aims will provide novel in...

## Key facts

- **NIH application ID:** 10388770
- **Project number:** 2R01AI123176-06
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Chandrashekhar Pasare
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $477,000
- **Award type:** 2
- **Project period:** 2016-12-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10388770

## Citation

> US National Institutes of Health, RePORTER application 10388770, Innate mechanisms of regulation of Th17 responses (2R01AI123176-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10388770. Licensed CC0.

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