# Unraveling the tolerogenic potential of lymph node fibroblastic reticular networks in autoimmune diabetes

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $602,531

## Abstract

Project Summary:
Type 1 diabetes results from impaired central and peripheral tolerance mechanisms. β-cell antigen-reactive T
cells escape negative selection in the thymus and regulation/deletion in the periphery. While the role and
therapeutic potential of professional antigen-presenting cells and regulatory T cells in maintaining peripheral
tolerance in type 1 diabetes is known, non-professional antigen presenting stromal cells residing in lymph nodes
remain understudied. For maintaining and therapeutically promoting peripheral tolerance to self-antigens such
as type 1 diabetes-relevant ones, these stromal cells present unique advantages over other antigen-presenting
cells due to their lower costimulatory to coinhibitory molecules ratio, which remains stable during inflammation
unlike activated professional antigen-presenting cells.
Our focus is on fibroblastic reticular cells (FRCs) which construct the lymph node stromal scaffold crucial for
lymph node expansion during immune responses. FRC presentation of artificial antigens to specific T cells in
lymph nodes lead to T cell deletion. Our studies showed that in the non-obese diabetic mouse model of type 1
diabetes, and in pancreatic lymph nodes from pancreatic organ donors with type 1 diabetes, the expression of
the autoantigen insulin, the relative frequency of FRCs, and the FRC reticular remodeling properties are
decreased. Thus, we hypothesize that peripheral expression and presentation of tissue-specific antigens by
FRCs to autoreactive T cells may contribute to peripheral tolerance. To test our hypothesis that lymph node
FRCs contribute to peripheral tolerance in type 1 diabetes, we have developed new mouse models to inhibit or
enhance the capability of lymph node FRCs to express and present self and type 1 diabetes-relevant antigens.
In Aim 1, we will evaluate the impact of these modifications on autoimmunity.
Additionally, to test FRCs’ ability to target autoreactive T cells and reduce autoimmunity, we propose innovative
in vitro co-culture models with HLA-matched human cells in Aim 2. These studies are based on our preliminary
data using murine FRCs. We demonstrated that (i) we can engineer FRC reticula that recapitulate FRC reticula
organization and phenotype in lymph nodes, and (ii) genetically engineered FRC reticula to express and present
type 1 diabetes-relevant antigens promote specific T cell anergy and regulatory T cells induction and expansion
in vitro. Here, we will test the capability of human lymph node-derived FRCs to provide similar immunomodulatory
effects on HLA-matched human T cells leading to decreased cytotoxicity on primary and stem cell-derived HLA-
matched β-cells for translatability.
While the proposed studies are focused on the specific role and therapeutic application of lymph node FRCs in
autoimmunity, our innovative immunoengineering approaches can be applied to the study of other lymphoid and
mesenchymal stromal cells. The interdisciplinary nature of our MPI...

## Key facts

- **NIH application ID:** 10998368
- **Project number:** 1R01DK141150-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Remi J Creusot
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $602,531
- **Award type:** 1
- **Project period:** 2024-07-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998368

## Citation

> US National Institutes of Health, RePORTER application 10998368, Unraveling the tolerogenic potential of lymph node fibroblastic reticular networks in autoimmune diabetes (1R01DK141150-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10998368. Licensed CC0.

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