Proximal Negative Feedback as a Mechanism for Post Thymic T cell Selection
ORAL · Invited
Abstract
Cytokine mediated interactions in the immune system are proximal in nature, extending only a few cell diameters from a site of production. Rather than being controlled by a centralized hub, immune responses proceed as an ensemble of self-organized transient neighborhoods with different cellular and biochemical compositions.
Regulatory niches are transient structures where antigen-presenting cells (APCs), conventional T cells (Tconvs), and regulatory T cells (Tregs) interact in spatially localized niches. Tconvs produce IL-2 and can proliferate when their T cell receptor (TCR) binds to specific peptides, while IL-2-driven Tregs suppress T cell activation in a negative feedback loop. This balance between TCR signaling strength and Treg suppression determines whether a T cell clone expands or not.
Effective immune responses require expanding high-affinity T cell clones while preserving diversity to avoid immune evasion. Canonical models suggest higher-affinity clones outgrow weaker ones in a natural selection-like process. However, natural selection is slow and tolerates transient proliferation of weak clones, contrasting with the rapid, regulated T cell expansion observed in secondary lymphoid organs.
Within regulatory niches, suppression acts in cis (on the activated T cell) and in trans (on neighboring T cells). We hypothesize these niches act as distributed selection centers, favoring high-affinity clones while suppressing weaker ones. This dynamic fosters a potent systemic response enriched with strong clones while maintaining clonal diversity.
To test this, we combined theoretical models with experimental studies. Models revealed how niche feedback enriches high-affinity clones while suppressing weaker ones. Predictions were tested using in vitro and in vivo experiments tracking T cell expansion with or without trans-suppression. These findings show how regulatory niches balance clone enrichment with diversity, shaping the immune repertoire.
Regulatory niches are transient structures where antigen-presenting cells (APCs), conventional T cells (Tconvs), and regulatory T cells (Tregs) interact in spatially localized niches. Tconvs produce IL-2 and can proliferate when their T cell receptor (TCR) binds to specific peptides, while IL-2-driven Tregs suppress T cell activation in a negative feedback loop. This balance between TCR signaling strength and Treg suppression determines whether a T cell clone expands or not.
Effective immune responses require expanding high-affinity T cell clones while preserving diversity to avoid immune evasion. Canonical models suggest higher-affinity clones outgrow weaker ones in a natural selection-like process. However, natural selection is slow and tolerates transient proliferation of weak clones, contrasting with the rapid, regulated T cell expansion observed in secondary lymphoid organs.
Within regulatory niches, suppression acts in cis (on the activated T cell) and in trans (on neighboring T cells). We hypothesize these niches act as distributed selection centers, favoring high-affinity clones while suppressing weaker ones. This dynamic fosters a potent systemic response enriched with strong clones while maintaining clonal diversity.
To test this, we combined theoretical models with experimental studies. Models revealed how niche feedback enriches high-affinity clones while suppressing weaker ones. Predictions were tested using in vitro and in vivo experiments tracking T cell expansion with or without trans-suppression. These findings show how regulatory niches balance clone enrichment with diversity, shaping the immune repertoire.
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Presenters
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Alon Oyler-Yaniv
Harvard Medical School
Authors
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Alon Oyler-Yaniv
Harvard Medical School
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Max Brambach
Harvard Medical School
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Jennifer Oyler-Yaniv
Harvard Medical School