Biology subjects

Helbich, S. S.

Publications and source records attributed to Helbich, S. S..

3 recordsLinked to original sources

bioRxiv2026

Treg-derived IκBζ promotes their conversion into Th2-like effectors and drives type 2 inflammation via BATF

Regulatory T cells (Treg cells) maintain peripheral immune tolerance but display considerable plasticity in peripheral tissues. The molecular mechanisms governing their function and plasticity, particularly under inflammatory conditions, remain poorly defined. Here, we identify the NF-{kappa}B-associated transcriptional cofactor I{kappa}B{zeta} as a critical regulator of Treg cell plasticity and function. Enforced expression of I{kappa}B{zeta} in Treg cells triggered the excessive expansion of functionally impaired Treg cells, resulting in lymphadenopathy, splenomegaly, and systemic type 2 inflammation, most prominently in the lung. Mechanistically, I{kappa}B{zeta} modified BATF expression and function, thereby driving the cell-intrinsic production of Th2-associated cytokines by Treg cells. Conversely, Treg-specific deletion of I{kappa}B{zeta} constrained IL-33-mediated expansion of tissue Treg cells and surprisingly attenuated type 2 inflammation. Thus, I{kappa}B{zeta} functions as a molecular switch that reprograms regulatory T cells into Th2-like Treg cells, thereby perturbing peripheral immune tolerance. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/707402v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1ef0b17org.highwire.dtl.DTLVardef@c12eaaorg.highwire.dtl.DTLVardef@decc86org.highwire.dtl.DTLVardef@1458767_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Single-cell chromatin landscape and DNA methylation patterns reveal shared molecular programs in human tumor and non-tumor tissue CCR8+ Treg cells

Regulatory T (Treg) cells, a subset of CD4+ T cells, play a crucial role in immunoregulation. Notably, CCR8-expressing Treg cells in tissues also contribute to organ homeostasis and repair. To determine whether these tissue-regenerative programs are active in the tumor microenvironment, we employed single-cell chromatin accessibility and genome-wide DNA methylation analyses to investigate CCR8+ tissue Treg cells isolated from human tumor and adjacent tumor-free tissues. Our findings indicate that CCR8+ tissue Treg cells from tumor and corresponding tumor-free tissues exhibit a high degree of similarity, suggesting that the tumor microenvironment may harbor highly activated tissue Treg cells. This observation was consistent across various tumor types and origins, including primary tumors and metastases. Using quantitative proteomics, we identified several candidate factors associated with the regenerative and suppressive programs of Treg cells, which may serve as potential reservoir of druggable targets for future therapeutic interventions.

immunology↗

bioRxiv2025

Functional Dichotomy of Developmental Foxp3+ Treg Cell Subsets in the Visceral Adipose Tissue of Lean and Obese Mice

Chronic inflammation and loss of Foxp3+ regulatory T (Treg) cells in the visceral adipose tissue (VAT) are hallmarks of the pathogenesis of insulin resistance and obesity. This study explores the roles of VAT Treg cells from thymic (tTreg) and peripheral (pTreg) developmental origin, revealing their opposing roles in metabolic inflammation. Obesity destabilized VAT tTreg cells, causing them to clonally expand into obesogenic Foxp3-IFN-{gamma}+ T effector cells, enhancing pro-inflammatory type 1 responses. Genetic tTreg ablation prevented this shift, promoting anti-inflammatory type 2 response, reduced body weight, and improved insulin resistance. Compared to their tTreg counterpart, pTreg cells were functionally well adapted to maintain VAT homeostasis and protect against obesity. Genetic pTreg ablation promoted spontaneous obesity symptoms even with physiological calorie intake, and worsened VAT inflammation and liver steatosis on a high-calorie diet. These findings highlight tTreg instability as a pathogenic threat and pTreg cells as crucial regulators of metabolic homeostasis. HighlightsO_LIVAT Tregs of lean mice originate from both thymic and peripheral Treg development C_LIO_LIHigh-calorie diet destabilizes tTregs that clonally expand into obesogenic IFN-{gamma}+ Th1 cells C_LIO_LIGenetic tTreg deficiency improves steady-state metabolism and prevents diet-induced obesity C_LIO_LIGenetic pTreg deficiency promotes obesity in both sexes even with normal calorie intake C_LIO_LIVAT pTregs are particularly adapted to regulate VAT homeostasis, including adipogenesis C_LI In BriefObesity and type 2 diabetes are characterized by insulin resistance, regulatory T (Treg) cell loss, and chronic inflammation in visceral adipose tissue (VAT). In this context, Yilmazer et al. dissect the functional roles of tTreg and pTreg cells. They show that VAT pTreg cells are particularly adapted to exert non-redundant homeostatic functions, and that pTreg deficiency predisposes to obesity even with normal calorie intake. In contrast, VAT tTreg cells can contribute to local inflammation by dedifferentiating into Foxp3- Th1-polarized effector cells. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/642664v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@19c740corg.highwire.dtl.DTLVardef@86d52borg.highwire.dtl.DTLVardef@152a88org.highwire.dtl.DTLVardef@19b7b13_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗