# How immunodominant Fc peptide epitopes expand natural regulatory T cells and downregulate inflammation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $436,272

## Abstract

Project summary
Recently, we characterized a natural regulatory T cell (nTreg) lineage that recognizes the heavy constant
region of immunoglobulin (Fc) very important in down-sizing the inflammation. Fc-specific nTreg can be found
in circulation in healthy donors but not in Kawasaki disease (KD) patients before high doses of intravenous
immunoglobulin (IVIG) therapy or in Rheumatoid Arthritis patients.
KD is a self-limited, T cell-mediated acute vasculitis that is the most common cause of acquired pediatric heart
disease. Coronary artery abnormalities (CAA) occur in up to 25% of untreated children but can be largely
prevented by timely administration of IVIG. We showed that damage to the arterial wall was associated with
failure to expand the Fc-specific nTreg population after IVIG, hence establishing an inverse correlation
between the numbers of Fc-specific nTreg and CAA.
Notably, Fc-specific nTreg were undetectable in all acute KD patients prior to IVIG and in adult patients who
had a remote history of KD in childhood. Following IVIG administration, KD patients with normal coronary
arteries have detectable Fc-specific nTreg in the circulation, but patients with CAA+ do not. Thus, the
expansion of Fc-specific nTreg appears to play a hitherto unappreciated protective role in vasculitis and is a
new mechanism of action of IVIG.
Preliminary studies in healthy donors and RA patients indicate that immunodominant Fc peptides can be
identified and include pan-HLA binders. In RA, the nTreg response to the whole Fc protein was low or absent
similar to KD children who develop CAA despite IVIG therapy.
This study will define the molecular basis of Fc-specific nTreg recognition and a possible defect in the antigen
processing of the endogeneous Fc presented by IgG+ B cells in KD children who develop CAA. The proposed
experiments will reveal the immunodominant minimal peptide epitopes of the Fc recognized by the nTreg in 70
KD patients after IVIG therapy, will unveil the immunodominant peptides endogenously presented by IgG+ B
cells to nTreg, and will evaluate the nTreg potency in down-regulating pro-inflammatory T cells.
The study will characterize the nTreg population in infants and young children for whom the immune regulation
is critical during the selection of T cell responses to the neoantigens that they encounter after birth without
experiencing undue inflammation. Thus, the study will have implications for control of inflammation beyond KD
as a disease model. Down-regulations of inflammation induced by immunomodulatory peptides recognized by
nTreg may later be developed as a novel anti-inflammatory therapy not only for KD children, but with a broader
application to autoimmune diseases including RA, and neurological diseases, including Alzheimer's, multiple
sclerosis and narcolepsy where IVIG has been proven successful.

## Key facts

- **NIH application ID:** 9852975
- **Project number:** 5R01AI143586-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** ALESSANDRA I FRANCO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $436,272
- **Award type:** 5
- **Project period:** 2019-01-23 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852975

## Citation

> US National Institutes of Health, RePORTER application 9852975, How immunodominant Fc peptide epitopes expand natural regulatory T cells and downregulate inflammation (5R01AI143586-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9852975. Licensed CC0.

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