The immune system preserves organismal integrity through the precise recognition of peptide–MHC complexes by T cells. MHC class I and class II molecules coordinate the selection, activation, and maintenance of CD8⁺ cytotoxic and CD4⁺ helper or regulatory T cells, linking immune defense with self-tolerance. Once regarded as static antigen display platforms, MHC molecules are now recognized as dynamically regulated by cellular context, cytokine signaling, and tissue-specific cues. Recent advances in single-cell and spatial transcriptomics reveal that both MHC I and II expression are fine-tuned by metabolic and inflammatory states, creating spatially distinct patterns of antigen presentation across organs. These spatial patterns appear to encode the immune history and physiological tone of tissues —an immune engram that integrates defence, tolerance, and repair. Defining how MHC-dependent presentation establishes and modifies these engrams will illuminate new principles of immune homeostasis and provide a framework for targeting tissue-specific immunity

Although MHC molecules were discovered more than half a century ago as central regulators of immune recognition, their roles in sustaining tissue homeostasis and tolerance remain only partially understood. MHC class I and II molecules not only guide thymic selection and the establishment of self-tolerance but also maintain peripheral equilibrium by shaping antigen presentation within local tissue niches. Recent single-cell and spatial multi-omics studies have overturned the long-held notion that MHC expression is static and cell-type restricted. Instead, both MHC I and II are dynamically regulated by metabolic, cytokine, and microenvironmental signals, forming spatially distinct antigen-presentation networks. These advances call for a unified framework to interpret how MHC-dependent communication encodes the “immune engram,” linking antigen recognition to immune memory, repair, and tolerance. This Research Topic aims to integrate mechanistic and spatial perspectives, spanning from thymic education to tissue remodeling, to redefine antigen presentation as a central organizer of immune–tissue interactions in health, autoimmunity, infection, and cancer.

This Research Topic aims to explore how MHC-dependent antigen presentation shapes immune regulation from central tolerance to tissue homeostasis. We welcome contributions that integrate molecular, cellular, and systems-level insights into the dynamic nature of antigen presentation and its impact on T cell function and tissue adaptation.
Subtopics may include, but are not limited to:
>Mechanisms of thymic selection and self-antigen expression in central tolerance
>Context-dependent regulation of MHC I and II in tissue environments
>Antigen presentation during inflammation, repair, and regeneration
>Crosstalk between antigen-presenting cells, regulatory T cells, and tissue-resident lymphocytes
>Metabolic and cytokine control of antigen processing and presentation
>Comparative and evolutionary perspectives on self-recognition and immune resilience
By uniting advances from developmental and tissue immunology, this collection seeks to establish a conceptual continuum linking antigen presentation, immune tolerance, and homeostatic memory across biological scales.

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Antigen Presentation in Thymic Selection, Immune Tolerance, and Tissue Homeostasis