TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo

Abstract

T cell receptor (TCR) ligation is required for the extrathymic differentiation of forkhead box p3+ (Foxp3+) regulatory T cells. Several lines of evidence indicate that weak TCR stimulation favors induction of Foxp3 in the periphery; however, it remains to be determined how TCR ligand potency influences this process. We characterized the density and affinity of TCR ligand favorable for Foxp3 induction and found that a low dose of a strong agonist resulted in maximal induction of Foxp3 in vivo. Initial Foxp3 induction by weak agonist peptide could be enhanced by disruption of TCR–peptide major histocompatibility complex (pMHC) interactions or alteration of peptide dose. However, time course experiments revealed that Foxp3-positive cells induced by weak agonist stimulation are deleted, along with their Foxp3-negative counterparts, whereas Foxp3-positive cells induced by low doses of the strong agonist persist. Our results suggest that, together, pMHC ligand potency, density, and duration of TCR interactions define a cumulative quantity of TCR stimulation that determines initial peripheral Foxp3 induction. However, in the persistence of induced Foxp3+ T cells, TCR ligand potency and density are noninterchangeable factors that influence the route to peripheral tolerance.

CD8+Foxp3+ T cells share developmental and phenotypic features with classical CD4+Foxp3+ regulatory T cells but lack potent suppressive activity

“…RA could overcome DC-mediated inhibition to some extent (data not shown), similar to previous findings with CD4 1 Foxp3 1 Tregs [22]. TCR ligand density and potency might, however, additionally influence Foxp3 induction [32]. Our results are in harmony with a study from Mucida et al where CD8 1 OTI cells were cultured with identical factors but in the presence of DC to induce Foxp3 [33].…”

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

“…T cells are known to discriminate between normal and infected or cancerous cells based on differences in pMHC affinity (2,3). It is also appreciated that the pMHC dose determines, for example, the peripheral induction of regulatory T cells (4,5). Although the proteins that form the TCRregulated signaling network have been identified (6,7), it remains unclear how the architecture they form integrates the pMHC affinity and dose into T-cell activation (8,9).…”

Enhancement of antigen-specific Treg vaccination in vivo

“…With regard to mechanisms it became clear that Treg conversion in vivo is best achieved by subimmunogenic delivery of strong agonists under conditions that avoid functional activation of antigen presenting cells (5)(6)(7)(8)(9). Also, in accordance with more recent data (10), in this setting, best conversion is seen in T cells that undergo only limited proliferation, whereas higher doses of the strong agonist result in more extensive proliferation and diminished conversion (5).…”