# Microbiota-mediated T cell tolerance in newborn and adult autoimmunity-prone mice

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $462,299

## Abstract

SUMMARY. Instruction of T cells to be tolerant to self occurs in the thymus through interactions of thymocytes
with the epithelial cell compartment. While the thymus serves as the primary site of immunologic T cell
tolerance to self-antigens and production of thymic T regulatory (tTreg) cells, microbial communities in the
gut also regulate the function of T effector (Teff) cells and production of peripheral Treg cells (pTreg).
Microbial colonization of mucosal tissues in early life facilitates tolerance to commensal and environmental
antigens. Abnormal colonization during this period can have long-term consequences contributing to
development of mucosal and systemic disease later in life. The mechanisms that regulate perinatal immune-
system-microbiota interactions to achieve long-term homeostasis are poorly defined. We previously
generated mice (Traf6ΔTEC) whose thymus was devoid of medullary thymic epithelial cell (mTECs). mTEC
depletion had a two-faceted effect on the T cell output: generation of autoreactive T cells and a 50% reduction
in the numbers of tTregs. The reduction in tTregs in Traf6ΔTEC mice in turn associated with: 1) reduced
numbers of Foxp3+ Tregs and T follicular (Tf) cells in the Peyer’s Patches (PP) of the small intestine and
small intestinal inflammation; 2) skewed production of IgA-coated bacteria; and 3) altered microbial
composition in the gut of knockout animals. Together, these results suggest that the aberrant T cell
compartment generated in the thymus of Traf6ΔTEC mice and associated changes in the microbiota
may adversely impact survival of newborn Traf6ΔTEC mice. In this proposal we will use the Traf6ΔTEC
mouse model to better understand how T cells and the gut microbiota influence each other to establish
perinatal organ-specific tolerance. We will test the following hypothesis: Impaired tTreg cell selection in
Traf6ΔTEC mice, induces changes in their gut microbiota that cannot support induction of perinatal tolerance
and viable progeny. Perinatal exposure of knockout pups to normal microbiota is required for tolerance
induction and survival. To test this hypothesis we will: 1) examine whether exposure to normal microbiota is
sufficient for promoting survival of newborn Traf6ΔTEC mice and identify microbial communities from WT
mice that rescue Traf6ΔTEC neonate survival; 2) examine whether induction of neonatal tolerance is
compromised in newborn Traf6ΔTEC mice that are not exposed to normal microbiota; and 3) examine if the
altered T cell compartment of Traf6ΔTEC mice acts as a genetic determinant of intestinal dysbiosis and
neonatal lethality. Defining early-life tolerance mechanisms could have a profound impact on our
understanding of human autoimmune disease development and may help us devise novel strategies for
managing and/or treating T cell mediated autoimmune diseases.

## Key facts

- **NIH application ID:** 10463592
- **Project number:** 5R01AI144903-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** KONSTANTINA ALEXANDROPOULOS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $462,299
- **Award type:** 5
- **Project period:** 2019-09-19 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463592

## Citation

> US National Institutes of Health, RePORTER application 10463592, Microbiota-mediated T cell tolerance in newborn and adult autoimmunity-prone mice (5R01AI144903-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10463592. Licensed CC0.

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