Differentiation of T-regulatory type 1 cells into an immunoregulatory Foxp3+ subset distinct from conventional FoxP3+ T-regulatory cells

T-regulatory type-1 (TR1) cells are a subset of interleukin-10-producing but FoxP3-negative Treg cells that arise in vivo in response to chronic antigenic stimulation. We have shown that repetitive systemic delivery of autoimmune disease-relevant peptide-major histocompatibility complex class II (pMHCII)-coated nanoparticles (pMHCII-NP) triggers the formation of large pools of disease-suppressing Foxp3– TR1 cells from cognate T-follicular helper (TFH) cell precursors. Here we show that these Foxp3– TR1 cells spontaneously differentiate into a novel immunoregulatory Foxp3+ TR1 subset that inherits transcriptional and epigenetic hallmarks of their precursors and is distinct from other Foxp3+ Treg cell subsets described to date. Development of this novel Foxp3+ Treg cell subset, as is also the case for Foxp3– TR1 cells but not conventional Foxp3+ Treg cells, is BLIMP1-dependent. In a model of central nervous system autoimmunity, deletion of Il10 in the Foxp3+ TR1 subset, but not its FoxP3+ counterpart, reduces the therapeutic activity of pMHCII-NPs without impairing their pharmacodynamic activity. T cell-specific deletion of Prdm1 and deletion of Il10 in both the FoxP3– and FoxP3+ TR1 subsets almost completely abrogate the therapeutic activity of these compounds. Thus, the TFH-TR1 transdifferentiation pathway evolves through 4 distinct cellular states that culminate in the generation of IL-10-producing FoxP3– and FoxP3+ TR1 subsets in a BLIMP1-dependent manner. This transdifferentiation pathway represents a new target for therapeutic intervention in immunity and autoimmunity.