# INNATE MECHANISMS OF REGULATION OF MEMORY TH17 CELL RESPONSES

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $397,500

## Abstract

Project Summary
The innate immune system has several families of pattern recognition receptors to detect invading pathogens
and initiate inflammatory responses to rapidly eliminate the pathogen. The innate immune system also plays
an instructive role in induction of adaptive immune responses against virulent pathogens. Toll-like receptors
(TLR) are one such family of receptors and their activation in cells of the innate immune system, such as
dendritic cells and macrophages, induces secretion of several pro-inflammatory cytokines such as IL-6, IL-12,
TNFα, etc. Many of these cytokines play an important role in T cell activation and differentiation. TLR activation
also leads to synthesis of a second family of cytokines comprised of IL-1 and IL-18 which are cleaved into
active forms and secreted following activation of a different family of cytosolic receptors called NOD like
receptors (NLRs). The cytokines IL-1 and IL-18 have major influence in directing T cell activation and
differentiation and more importantly use the same signaling components as the TLR signaling pathway. It is
becoming clear that IL-1 and IL-18 are the major players in innate control of adaptive immunity and the
mechanisms by which they regulate T cell activation and differentiation are not completely understood. Our
previous work has shown that IL-R mediated MyD88 dependent signaling is critical for Th17 lineage
differentiation in systemic and mucosal immune systems. Th17 cells are crucial for fighting fungal and
extracellular bacterial infections and have also been implicating in causing auto-immune diseases such as
Rheumatoid Arthritis and Inflammatory Bowel Disease. It is therefore crucial to understand the cellular and
molecular mechanisms by which these cells are regulated. In our new studies we have found that IL-1 plays a
critical role in regulating effector functions of already primed Th17 memory T cells. We propose to build on
these findings and gain a deeper understanding of how IL-1 regulates functioning of Th17 cells and elucidate
the physiological significance of IL-1 mediated regulation of Th17 effector functions. In Aim 1, we will
understand of the cellular and molecular mechanisms by which IL-1 is made during dendritic cell-memory Th17
cell interactions. In Aim 2, we will elucidate the signaling and molecular mechanisms by which IL-1R signaling
in T cells impacts production of IL-17 and related family of cytokines. In Aim 3, we will use in vivo approaches
to understand the importance of IL-1R signaling in memory Th17 cell function and examine the role of IL-1 in
reactivation of pathogen specific memory Th17 cells as well as memory Th17 cells that cause auto-immunity .
These studies will significantly advance our understanding of the role of IL-1 family of cytokines in regulation
of CD4 T cell functions. Further more, unraveling the molecular mechanisms by which IL-1 family of cytokines
regulate effector and memory T cell functions will not only enhance our und...

## Key facts

- **NIH application ID:** 9828746
- **Project number:** 5R01AI123176-04
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Chandrashekhar Pasare
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,500
- **Award type:** 5
- **Project period:** 2016-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828746

## Citation

> US National Institutes of Health, RePORTER application 9828746, INNATE MECHANISMS OF REGULATION OF MEMORY TH17 CELL RESPONSES (5R01AI123176-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828746. Licensed CC0.

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