# Phosphatases in Systemic Autoimmunity

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2022 · $437,500

## Abstract

Abstract
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Systemic lupus erythematosus (SLE) presents profound T cell effector dysfunction. Interleukin-2
(IL-2) deficiency accounts for the increased infection-related morbidity and mortality rates, the
defective regulatory cell (Treg) function and compromised ability to eliminate autoreactive T
cells. In parallel, T cells produce increased amounts of interleukin-17 (IL-17) which is involved
in tissue inflammation and damage. Protein phosphatase 2A (PP2A) is the first serine/threonine
phosphatase recognized to contribute first to human SLE and later to murine lupus
immunopathology. It is a trimolecular enzyme consisting of scaffolding, catalytic and regulatory
subunits. We have shown that PP2Ac expression is increased in patients with SLE and that it is
central to a number of signaling pathways including the suppression of the production of IL-2
and the enhancement of the production of IL-17 and that the regulatory subunit Bβ regulates IL-
2 deprivation-induced T cell death and is decreased in SLE patients. A mouse lacking PP2A in
Tregs develops severe inflammation and autoimmunity because PP2Ac is needed for the
suppression of the mTORC1 pathway. Using novel mice and molecular tools the proposed
work will test the hypothesis that PP2Ac represents a main contributor in the
immunopathogenesis of SLE and autoimmunity in general by 1) determining the importance of
PP2A expression in Tregs in the regulation of the autoimmune response and related pathology;
2) determining the importance of PP2A expression in conventional T cells in the regulation of
the autoimmune response and related pathology; and 3) establishing the aberrant expression of
the regulatory subunit Bα in human SLE and determine how it contributes to IL-17 production.
This project will generate novel concepts (differential regulation of central immune functions by
PP2A, regulation of distinct functions by specific regulatory subunits) and new informative mice
(mice lacking PP2A in T cell subsets and mice lacking regulatory subunits in T cells).
Understanding the molecular complexity which underlies the expression of systemic
autoimmunity is significant to the extent we wish to correct important pathways to treat patients.
The ability to carry out parallel studies in mice and humans increases significantly the
translational value of our work.
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## Key facts

- **NIH application ID:** 10468134
- **Project number:** 5R01AI136924-05
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** George C Tsokos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $437,500
- **Award type:** 5
- **Project period:** 2018-09-18 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468134

## Citation

> US National Institutes of Health, RePORTER application 10468134, Phosphatases in Systemic Autoimmunity (5R01AI136924-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10468134. Licensed CC0.

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