FGF21, induced by ER stress, maintains mTEC function and central immune tolerance in mice
Background
The breakdown of central immune tolerance within the thymus is a fundamental cause of autoimmune conditions like Type 1 Diabetes Mellitus (T1DM). Medullary thymic epithelial cells (mTECs) are crucial for this process, expressing diverse tissue-restricted antigens (TRAs) via the Autoimmune Regulator (AIRE) protein to eliminate self-reactive thymocytes. Fibroblast growth factor 21 (FGF21) is primarily known as a metabolic hormone produced by the liver, regulating metabolism under nutritional and cellular stress through fibroblast growth factor receptor 1c (FGFR1c) and its co-receptor β-Klotho. However, its role in thymic immune homeostasis and specifically in mTEC function, which is critical for preventing autoimmunity, has been largely unexplored.
Study Design
Researchers investigated the role of FGF21 in thymic immune homeostasis using Fgf21-deficient mice. They assessed the impact of FGF21 deficiency on peripheral autoimmune responses, as well as the number and function of mTECs. The study also explored the mechanisms by which FGF21 expression is regulated within mTECs, specifically focusing on the involvement of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathways. They examined how FGF21 influences clonal deletion of self-reactive thymocytes in cooperation with thymic dendritic cells, and its role in maintaining mTEC integrity and protein homeostasis.
Results
FGF21, while predominantly hepatic, was found to be locally expressed by mature mTECs and significantly contributes to central immune tolerance. Fgf21-deficient mice exhibited exacerbated peripheral autoimmune responses, highlighting FGF21's protective role. FGF21 supported both the number and function of mTECs, and importantly, promoted clonal deletion of self-reactive thymocytes in conjunction with thymic dendritic cells. In mature mTECs, endoplasmic reticulum (ER) stress induced FGF21 expression through unfolded protein response (UPR) pathways. FGF21 was observed to act preferentially within the mature mTEC compartment as a stress-responsive metabolic regulator, downstream of the integrated stress response.
Key Findings
- FGF21 is locally expressed by mature medullary thymic epithelial cells (mTECs) and contributes to central immune tolerance.
Fgf21-deficient miceexhibited exacerbated peripheral autoimmune responses.- FGF21 supports mTEC number and function, promoting clonal deletion in the thymus.
- Endoplasmic reticulum (ER) stress induces FGF21 expression in mTECs via
unfolded protein responsepathways. - FGF21 maintains mTEC integrity and central tolerance by limiting sustained stress and preserving
protein homeostasis.
Why It Matters
This research identifies FGF21 as a novel, local regulator of thymic immune homeostasis, expanding its known roles beyond metabolic regulation. Targeting FGF21 could offer a new therapeutic strategy for autoimmune diseases by enhancing or restoring central immune tolerance. For biohackers and clinicians, understanding FGF21's role in mTEC function suggests potential avenues for modulating thymic output and preventing autoimmunity, though this is a preclinical finding. The discovery that ER stress induces FGF21 in mTECs also opens up possibilities for interventions that modulate cellular stress responses to support thymic health. This work is foundational, indicating that a usable protocol for human application is still far off, requiring extensive further research.
fgf21
immune-tolerance
autoimmune-disease
thymus
mtec
er-stress