# Tpl2 regulation of pDC function and SLE pathogenesis

> **NIH NIH R21** · UNIVERSITY OF GEORGIA · 2021 · $193,340

## Abstract

Abstract
Systemic lupus erythematosus (SLE) is a painful, chronic autoimmune disease estimated to affect up to
150/100,000 people with an increased prevalence in young women. It results from disruption in normal immune
tolerance mechanisms leading to activation of autoreactive T cells, expansion of autoreactive B cells, circulating
autoantibodies and immune complex deposition. Current treatments consist primarily of high dose corticosteroids
and immunosuppressive drugs that help to manage symptoms but fail to address the underlying cause and are
associated with adverse side effects. Therefore, novel immunotherapeutic interventions are needed. Type I IFNs
and the plasmacytoid dendritic cells (pDCs) that secrete them have emerged as key players in the pathogenesis
of SLE. Immune cells from most SLE patients are imprinted with a type I IFN gene signature. Therefore, blockade
of type I IFNs, their receptors and pDCs are being actively pursued as immunotherapies for SLE and other
autoimmune diseases imprinted with IFN signatures. Despite the important immunological functions of pDCs,
relatively little is understood about their molecular ‘wiring’ that controls IFN production, which presents a barrier
to developing novel pDC-targeted immunotherapies. Herein, we provide evidence that the serine-threonine
kinase, Tpl2 (also known as MAP3K8 or COT), is essential for TLR-induced type I IFN production by pDCs in
vivo. The objective of this application is to understand how Tpl2 is uniquely required by pDCs for nucleic acid-
induced IFN production and to determine whether Tpl2 expression in pDCs influences SLE pathogenesis. This
will be examined in two Aims. Aim 1 will combine ex vivo biochemical analysis of primary murine pDCs with
unbiased phosphoproteomics approaches to delineate the biochemical mechanisms by which Tpl2 promotes
type I IFN production in pDCs. Aim 2 will use an innovative mixed bone marrow chimera approach to determine
the contribution of Tpl2 expression within pDCs to SLE development a murine model. The expected outcome of
the proposed studies is a better understanding of the molecular mechanism(s) governing pDC nucleic acid
sensing and IFN production. This information will facilitate novel immunotherapeutic approaches to modulate
IFNs and/or pDCs for treating SLE and possibly other human interferonopathies.

## Key facts

- **NIH application ID:** 10242226
- **Project number:** 5R21AR075317-02
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Wendy T Watford
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $193,340
- **Award type:** 5
- **Project period:** 2020-08-19 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242226

## Citation

> US National Institutes of Health, RePORTER application 10242226, Tpl2 regulation of pDC function and SLE pathogenesis (5R21AR075317-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10242226. Licensed CC0.

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