Peripheral tolerance is not a static property of the immune system; it is a continuously tuned, tissue-distributed control problem. At any moment, each tissue niche imposes a local setpoint (or 'tone') along a continuum that spans sterilizing immunity, equilibrium, and tolerance. This tone emerges from the integration of antigen display, antigen-presenting cell (APC) state, cytokine and metabolic context, stromal and vascular cues, and a layered network of regulatory mechanisms including regulatory T cells (Tregs), anergy/exhaustion programs, and inhibitory checkpoint pathways. Keystone Epitope Theory (KET) reframes this control problem by proposing that each niche contains a small set of niche-calibrating peptide-HLA complexes that disproportionately allocate adaptive immune 'attention' and thereby shape both efferent tissue surveillance and afferent priming decisions. Within this broader operational category, keystone epitopes are the subset derived from TRAIT-defined keystone organisms and are expected to be the most reproducible, high-gain trainers of tissue-distributed immunity. Here, we review how peripheral tolerance can be understood as dynamic niche control, how Treg TCR specificity contributes to niche tone, and how inhibitory checkpoints differ from broader tolerance thresholds. We then apply this synthesis to the paradox of immune checkpoint inhibitor (ICI) toxicities: these toxicities often resemble familiar autoimmune syndromes, yet they differ in tempo, histopathology, serology, and clinical course. We argue that KET provides a tractable framework for explaining this 'phenotype resemblance with mechanistic disconnect' by emphasizing (i) antigen channel selection (niche-calibrating, including keystone, versus lowsalience channels), (ii) afferent versus efferent tolerance gates, and (iii) the role of altered-self and mimic epitopes that become visible under checkpoint blockade. Finally, we propose a lesion-anchored experimental roadmap and toolkit to test these models, integrating single-cell and spatial omics, TCR reconstruction, niche-calibrating (including keystone) and mimic epitope screening, dual tetramer validation, and structural immunology, enabling falsifiable links between tissue-specific injury and antigenic drivers and informing endotype-level prediction, prevention, and mechanism-aligned treatment of immune-related adverse events.
S. Mallal (Sat,) studied this question.