# Modulation of immune cell phenotype by hormone-producing epithelia in autoimmune endocrinopathies

> **NIH NIH K08** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $172,800

## Abstract

In autoimmune endocrine disease, self-reactive T cells inappropriately target hormone-producing cells, leading
to tissue damage and obliteration of hormone production. One of the most common autoimmune diseases,
Hashimoto’s thyroiditis, offers an ideal model to decipher how hormone production is lost in autoimmune
endocrine disease. Surprisingly, only 20-40% of patients with Hashimoto’s thyroiditis exhibit loss of hormone
production (hypothyroid). The remainder of patients retain hormone production despite immune infiltration of the
thyroid (euthyroid). Understanding how hormone production is preserved requires dissection of interactions
between infiltrating T cells and hormone-producing epithelial cells, such as thyrocytes. To address this challenge,
I have performed single-cell RNA sequencing in human thyroid from patients with Hashimoto’s thyroiditis,
Graves’ disease (an autoantibody-driven form of thyroid autoimmunity) and those without autoimmune thyroid
disease. We have identified a transcriptionally unique population of thyrocytes that is significantly expanded in
Hashimoto’s thyroiditis and ectopically expresses class II MHC. In addition, our preliminary data indicate several
thyroid-infiltrating CD4+ T cell populations that appear to distinguish Graves’ disease from Hashimoto’s
thyroiditis. Epithelial cells are known to express MHCII in inflamed tissue, however it is not known whether these
cells present antigen to CD4+ T cells in vivo. We hypothesize that MHCII+ thyrocytes present antigen to and
modulate the phenotype of CD4+ T cells, leading to global changes in the inflammatory environment. We further
hypothesize that the transcriptional phenotype of MHCII+ thyrocytes differs in euthyroid and hypothyroid
Hashimoto’s thyroiditis. To test these hypotheses, I will compare the transcriptional and functional phenotype of
MHCII+ thyrocytes in euthyroid and hypothyroid Hashimoto’s thyroiditis and Graves’ disease (Aim 1). I will then
determine how thyroid-infiltrating self-reactive T cells differ among these conditions (Aim 2). This project may
define how tissue function can be preserved in autoimmune disease more broadly.
This proposal presents a five-year plan for Dr. Michelle Rengarajan to train in immunology to decipher how
epithelial-immune interactions underly endocrine autoimmunity. Dr. Rengarajan will be an Instructor in Medicine
at Harvard Medical School (HMS) and Massachusetts General Hospital (MGH). She will perform the proposed
work under mentorship from Drs. Andrew Luster and Alexandra-Chloe Villani. Dr. Rengarajan has outlined a
career development plan focused on single-cell genomics, epithelial-immune interactions, antigen-specific T
cells, with additional training in scientific communication and leadership. Dr. Rengarajan’s long-term goal is to
develop an independent research program studying the mechanistic basis of autoimmune endocrinopathies. The
experiments and training plan outlined in this proposal, with the collaborativ...

## Key facts

- **NIH application ID:** 10505915
- **Project number:** 1K08DK133497-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Michelle Rengarajan
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $172,800
- **Award type:** 1
- **Project period:** 2022-09-30 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10505915

## Citation

> US National Institutes of Health, RePORTER application 10505915, Modulation of immune cell phenotype by hormone-producing epithelia in autoimmune endocrinopathies (1K08DK133497-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10505915. Licensed CC0.

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