Metabolic, epigenetic, or microenvironmental regulation of T cells in autoimmunity

T cells are central mediators of autoimmune disease pathogenesis, yet their functional states are not defined solely by antigen recognition or canonical lineage-determining transcription factors.
Recent advances have revealed that cellular metabolism, epigenetic regulation, and tissue microenvironmental cues are critical determinants of T cell differentiation, plasticity, and persistence in autoimmune settings.
Dysregulated nutrient sensing, mitochondrial function, and redox balance can promote pathogenic effector programs or destabilize regulatory T cell (Treg) identity. In parallel, epigenetic mechanisms—including chromatin accessibility, histone modifications, DNA methylation, and non-coding RNAs-establish durable transcriptional states that sustain immune dysregulation. Moreover, tissue microenvironments characterized by hypoxia, cytokine gradients, stromal and neural interactions, and microbiota-derived metabolites further reprogram T cell metabolism and epigenetic landscapes.
An integrated understanding of these regulatory layers is increasingly recognized as essential for explaining disease heterogeneity and therapeutic response in autoimmune disorders.

The goal of this Research Topic is to define how metabolic programs, epigenetic regulation, and tissue microenvironments converge to control T cell function in autoimmunity, and to highlight how disruption of these pathways drives pathogenic immune responses. While each regulatory layer has been extensively studied in isolation, their coordinated roles in shaping T cell fate, stability, and pathogenicity remain incompletely understood.

This Topic aims to move the field beyond descriptive phenotyping by encouraging studies that establish causal and mechanistic links between metabolic states, chromatin organization, and tissue-derived signals in autoreactive and regulatory T cells. By integrating insights across autoimmune diseases, this Research Topic seeks to identify shared regulatory principles as well as disease- and tissue-specific mechanisms that underlie immune dysfunction.

A further objective is to accelerate translational relevance, highlighting how metabolic and epigenetic pathways, or microenvironmental cues, may be therapeutically targeted to selectively restrain pathogenic T cells while preserving immune tolerance. Collectively, this Research Topic aims to provide a conceptual framework connecting molecular regulation to clinical heterogeneity, biomarker development, and emerging precision immunotherapies in autoimmunity.

This Research Topic welcomes original research, reviews, mini-reviews, perspectives, and method articles addressing the integrated regulation of T cells by metabolic, epigenetic, and microenvironmental mechanisms in autoimmune diseases.

Topics of interest include: metabolic reprogramming of effector and regulatory T cells; epigenetic mechanisms governing T cell plasticity, stability, and exhaustion; crosstalk between metabolism and chromatin regulation; and tissue-specific microenvironmental cues shaping T cell pathogenicity in organs such as kidney, gut, skin, central nervous system, lung, and synovium.

Studies employing single-cell or spatial multi-omics, metabolic flux analysis, lineage tracing, and systems immunology approaches are particularly encouraged. Translational studies linking these mechanisms to biomarkers, therapeutic response, or immune tolerance restoration are within scope. Both disease-focused and cross-disease studies are welcome.

Topic Editor Dr. Eri Katsuyama received honoraria from Astellas Pharma.

Topic Editor Dr. M. Kono reports grants and/or speaking fees from AbbVie, Asahi-Kasei, Astellas, AstraZeneca, Ayumi, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Gilead Sciences, GlaxoSmithKline, Janssen, Kowa, Kyocera, Lotte, Nippon Boehringer Ingelheim, Nippon Shinyaku, Mitsubishi Tanabe, Mochida, Pfizer, Sandoz, Taiju Life Social Welfare Foundation, Taisho, Takeda, Terumo, UCB Japan and Yamazaki Baking.

Topic Editor Dr. Marc Scherlinger reports being or having been a consultant for Abbvie, Amgen, AstraZeneca, Biogen, BMS, Celltrion, Fresenius, Galapagos, GSK, InnatePharma, Nordic Pharma, Novartis and Sandoz.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Classification
• Clinical Trial
• Conceptual Analysis
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Classification
• Clinical Trial
• Conceptual Analysis
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review
• Technology and Code

Keywords: Autoimmunity, T cell differentiation, T cell plasticity, Regulatory T cells (Tregs), Cellular metabolism, Metabolic reprogramming, Epigenetic regulation, Chromatin accessibility, Tissue microenvironment, Single-cell multi-omics, spatial multi-omics

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.