TCR recognition efficiencies shape the repertoire of CD4+ CD25high FOXP3+ regulatory T cells.
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The Treg antigenic niche controls tissue-residency, stability, and regulatory function in peripheral tissues.
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Tolerogenic vaccination and Treg-based immunotherapy reverse chronic autoimmune disease.
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Tregs mediate tolerance by mechanisms of bystander suppression and infectious tolerance.
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Intermediate-efficiency MHC-ligands, high-zone IFN-β, and low-zone IL-2 favor Treg responses.
Abstract
FOXP3+ regulatory T cells (Tregs) constitute a critical barrier that enforces tolerance to both the self-peptidome and the extended-self peptidome to ensure tissue-specific resistance to autoimmune, allergic, and other inflammatory disorders. Here, we review intuitive models regarding how T cell antigen receptor (TCR) specificity and antigen recognition efficiency shape the Treg and conventional T cell (Tcon) repertoires to adaptively regulate T cell maintenance, tissue-residency, phenotypic stability, and immune function in peripheral tissues. Three zones of TCR recognition efficiency are considered, including Tcon recognition of specific low-efficiency self MHC-ligands, Treg recognition of intermediate-efficiency agonistic self MHC-ligands, and Tcon recognition of cross-reactive high-efficiency agonistic foreign MHC-ligands. These respective zones of TCR recognition efficiency are key to understanding how tissue-resident immune networks integrate the antigenic complexity of local environments to provide adaptive decisions setting the balance of suppressive and immunogenic responses. Importantly, deficiencies in the Treg repertoire appear to be an important cause of chronic inflammatory disease. Deficiencies may include global deficiencies in Treg numbers or function, subtle ‘holes in the Treg repertoire’ in tissue-resident Treg populations, or simply Treg insufficiencies that are unable to counter an overwhelming molecular mimicry stimulus. Tolerogenic vaccination and Treg-based immunotherapy are two therapeutic modalities meant to restore dominance of Treg networks to reverse chronic inflammatory disease. Studies of these therapeutic modalities in a preclinical setting have provided insight into the Treg niche, including the concept that intermediate-efficiency TCR signaling, high IFN-β concentrations, and low IL-2 concentrations favor Treg responses and active dominant mechanisms of immune tolerance. Overall, the purpose here is to assimilate new and established concepts regarding how cognate TCR specificity of the Treg repertoire and the contingent cytokine networks provide a foundation for understanding Treg suppressive strategy.
Abbreviations
APC
Antigen Presenting Cell
CNS
Central Nervous System
CFA
Complete Freund's Adjuvant
Tcon
Conventional T Cell
DC
Dendritic Cell
EAE
Experimental Autoimmune Encephalomyelitis
FOXP3
Forkhead Box P3
FOXP3+
Regulatory T Cells (Tregs)
GM-CSF
Granulocyte-Macrophage Colony Stimulating Factor
IFN-β
Interferon-β
IL-2
Interleukin-2
CD25 or IL2Rα
Interleukin-2 Receptor-Alpha
MHC
Major Histocompatibility Complex
MHCI or MHCII
Major Histocompatibility Complex Class I or Class II