Circulating Vitamin D (Vit-D) has emerged as a potent immune modulator in asthma, yet its direct impact on TH2 cell regulation, the central effectors of allergic inflammation, remains unclear. Preliminary transcriptomic analysis of neonatal cord blood revealed that gestational Vit-D deficiency corresponds to elevated adaptive and innate immune responses, driven by TH2 immunity and antimicrobial responses related to asthma inflammation. To elucidate cell-specific molecular mechanisms of Vit-D, we differentiated murine TH2 cells in vitro under conditions mimicking Vit-D sufficiency and deficiency. Our findings demonstrate that Vit-D exposure promotes intracellular calcium ion homeostasis while suppressing prominent inflammatory cytokines characteristic of asthma. Conversely, Vit-D deficiency reprograms TH2 cell lineage commitment, inducing overexpression of cytolytic molecules and major histocompatibility complex (MHC) class I molecules-traits typically associated with cytotoxicity rather than the canonical helper function. Our findings underscore Vit-D's role in stabilizing TH2 cell function and fate, offering insights into asthma and autoimmune disorders.
© 2025 The Authors.

Th17 cells are critical for mucosal immunity, producing IL-17A, IL-17F, and IL-22, but dysregulated Th17 responses are implicated in autoimmune diseases. Despite their susceptibility to oxidative stress in certain conditions, Th17 cells exhibit reduced oxidative DNA damage and cell death compared to other T helper subsets. However, the mechanisms that protect Th17 cells from oxidative stress are poorly understood. Here, we identify Xeroderma Pigmentosum Complementation Group C (XPC) as a key regulator of DNA repair and genomic stability in Th17 cells. In XPC-deficient mice, we demonstrate that the absence of XPC impairs Th17 differentiation, as evidenced by reduced expression of key differentiation markers, including Rorc and Il17a, along with decreased IL-17A production. This deficiency leads to increased oxidative stress, DNA damage, and a metabolic shift from glycolysis to oxidative phosphorylation. Moreover, the transcription factor BATF directly regulates XPC expression, linking the BATF-XPC axis to the maintenance of Th17 cell function. Importantly, we find that restoring antioxidant capacity with N-Acetylcysteine (NAC) rescues IL-17A production and reduces DNA damage in XPC-deficient Th17 cells. Mechanistically, we find that XPC interacts with OGG1, a DNA glycosylase involved in the repair of oxidative DNA damage, highlighting XPC’s role in maintaining genomic integrity during Th17 cell differentiation. Our findings reveal a previously unrecognized role for XPC in protecting Th17 cells from oxidative stress, ensuring their proper differentiation and function, with potential implications for targeting DNA repair pathways in autoimmune and inflammatory diseases.

AIM2 is an interferon-inducible HIN-200 protein family member and is well-documented for its roles in innate immune responses as a DNA sensor. Recent studies have highlighted AIM2's function on regulatory T cells (Treg) and follicular T cells (Tfh). However, its involvement in Th17 cell differentiation remains unclear. This study reveals that AIM2 promotes Th17 cell differentiation. AIM2 deficiency decreases IL-17A production and downregulates key Th17 associated proteins (RORγt, IL-1R1, IL-23R). AIM2 is located in the nucleus of Th17 cells, where it interacts with RORγt, enhancing its binding to the Il17a promoter. The absence of AIM2 hinders naive CD4 T cells from differentiating into functional Th17 cells and from inducing colitis in Rag1-/- mice. This study uncovers AIM2's role as a regulator of Th17 cell transcriptional programming, highlighting its potential as a therapeutic target for Th17 cell-mediated inflammatory diseases.
© 2023 The Author(s).

Cell differentiation results in widespread changes in transcriptional programs as well as multi-level remodeling of three-dimensional genome architecture. Nonetheless, few synthetically investigate the chromatin higher-order landscapes in different T helper (Th) cells. Using RNA-Seq, ATAC-Seq and Hi-C assays, we characterize dynamic changes in chromatin organization at different levels during Naive CD4+ T cells differentiation into T helper 17 (Th17) and T helper 1 (Th1) cells. Upon differentiation, we observe decreased short-range and increased extra-long-range chromatin interactions. Although there is no apparent global switch in the A/B compartments, Th cells display the weaker compartmentalization. A portion of topologically associated domains are rearranged. Furthermore, we identify cell-type specific enhancer-promoter loops, many of which are associated with functional genes in Th cells, such as Rorc facilitating Th17 differentiation and Hif1a responding to intracellular oxygen levels in Th1. Taken together, these results uncover the general patterns of chromatin reorganization and epigenetic landscapes of gene regulation during T helper cell differentiation.
© 2023. The Author(s).

Fibroblasts have a considerable functional and molecular heterogeneity and can play various roles in the tumor microenvironment. Here we identify a pro-tumorigenic IL1R1+, IL-1-high-signaling subtype of fibroblasts, using multiple colorectal cancer (CRC) patient single cell sequencing datasets. This subtype of fibroblasts is linked to T cell and macrophage suppression and leads to increased cancer cell growth in 3D co-culture assays. Furthermore, both a fibroblast-specific IL1R1 knockout and IL-1 receptor antagonist Anakinra administration reduce tumor growth in vivo. This is accompanied by reduced intratumoral Th17 cell infiltration. Accordingly, CRC patients who present with IL1R1-expressing cancer-associated-fibroblasts (CAFs), also display elevated levels of immune exhaustion markers, as well as an increased Th17 score and an overall worse survival. Altogether, this study underlines the therapeutic value of targeting IL1R1-expressing CAFs in the context of CRC.
© 2023. The Author(s).