Biology subjects

Sun, I.-H.

Publications and source records attributed to Sun, I.-H..

3 recordsLinked to original sources

bioRxiv2026

Fezf2 regulates differentiation of Aire-expressing and post-Aire mimetic epithelial populations maintaining thymic homeostasis

Fezf2 has been proposed to serve principally as a transcriptional regulator of broad self-antigen expression in medullary thymic epithelial cells (mTECs). Here, we demonstrate an additional function for Fezf2 as a developmental regulator of TEC lineage commitment. Fezf2 deficiency in the thymus led to a relative expansion of lung mimetic and Ccl21+ immature mTECs at the expense of MHCII-hi Aire-expressing and all other mimetic populations. Consistent with this, the disruption of mTEC development had functional consequences, including alterations in tuft-associated iNKT polarization and microfold-associated B-cell class switching. In addition, high-resolution transcriptomics revealed that Fezf2 and Aire regulate distinct transcriptional programs, with Fezf2 driving both activation and repression of a more limited set of tissue-restricted genes compared to the broad gene activation program observed for Aire. Pure transcriptional repression at Fezf2 target loci was sufficient to partially rescue mTEC development in global Fezf2-/- (tKO) mice, potentially through suppression of Lifr expression and modulation of downstream Stat3 signaling tone. These results expand our understanding of Fezf2 in mTEC biology, highlighting transcriptional repression as a required functional facet for adult steady-state lineage patterning across the mTEC compartment.

immunology↗

bioRxiv2025

Transient Dietary Changes Modulate Inflammatory Disease Trajectory in the Lean State

Obesity potently alters immune responses across various inflammatory contexts1-7. However, it is unclear whether a transient high-fat diet (HFD) can affect immune function despite minimal effects on body weight. Here, we demonstrate that a short-term HFD regimen significantly exacerbates disease severity in a model of experimental psoriasis, comparable to what is observed in obese mice on long-term HFD. We find that a critical 4-day window of HFD coinciding with disease onset is sufficient to overactivate the immune response, leading to worsened disease outcomes. Mechanistically, we identify the CD4+ T cell compartment as an essential mediator of HFD-induced disease severity. Within the compartment, we functionally validate that disease exacerbation is driven by increased differentiation of a pathogenic population of T helper 17 (TH17) cells8 expressing IL1R1 (interleukin-1 receptor, type I)9, which is triggered by localized activation of the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome10. This brief window of HFD at disease onset leads to immune-dependent sensitization, as disease severity is increased upon a subsequent flare, despite complete recovery and under a low-fat diet (LFD) regimen. Our data indicate that transient dietary changes during the initial stages of an inflammatory event can rewire the immune milieu, profoundly influencing disease progression and inflammatory memory11. This phenomenon may have broad implications for conditions where obesity, and not diet itself, is considered the primary risk factor.

immunology↗

bioRxiv2019

Targeting glutamine metabolism enhances tumor specific immunity by inhibiting the generation of MDSCs and reprogramming tumor associated macrophages

Myeloid cells comprise a major component of the Tumor Microenvironment (TME) promoting tumor growth and immune evasion. By employing a novel small molecule inhibitor of glutamine metabolism not only were we able to inhibit tumor growth but we markedly inhibited the generation and recruitment of Myeloid Derived Suppressor Cells (MDSC). Targeting tumor glutamine metabolism led to a decrease in CSF-3 and hence recruitment of MDSC as well immunogenic cell death leading to an increase in inflammatory Tumor Associated Macrophages (TAMs). Alternatively, inhibiting glutamine metabolism of the MDSC themselves led to activation induced cell death and conversion of MDSC to inflammatory macrophages. Surprisingly, blocking glutamine metabolism also inhibited IDO expression of both the tumor and myeloid derived cells leading to a marked decrease in kynurenine levels. This in turn inhibited the development of metastasis and further enhanced anti-tumor immunity. Indeed, targeting glutamine metabolism rendered checkpoint blockade-resistant tumors susceptible to immunotherapy. Overall, our studies define an intimate interplay between the unique metabolism of tumors and the metabolism of suppressive immune cells.

immunology↗