iTreg

iTreg, short for inducible regulatory T cell, refers to a subset of CD4+ regulatory T cells generated from conventional naive T cells in the periphery in response to antigenic stimulation under tolerogenic conditions. Unlike thymus-derived Tregs (nTregs or tTregs), iTregs arise outside the thymus during ongoing immune responses and can populate mucosal tissues and sites of inflammation. The defining functional feature is the capacity to suppress autoreactive and effector T cell responses, helping maintain peripheral tolerance.

Induction of iTregs occurs both in vivo and in vitro. Differentiation is driven by T cell receptor signaling in the presence of transforming growth factor-beta (TGF-β) and interleukin-2 (IL-2). All-trans retinoic acid (ATRA) and related signals can enhance Foxp3 induction and stability. Inflammatory cytokines such as IL-6, IL-1β, or IL-21 can impede iTreg differentiation and promote Th17 development, reflecting the plasticity of this lineage. Foxp3 is the key transcription factor associated with regulatory function, but expression alone does not always guarantee stable regulatory activity.

Stability and epigenetics are important considerations. The methylation status of the Treg-specific demethylated region (TSDR) serves as a marker of regulatory lineage, with complete demethylation associated with stable Foxp3 expression. iTregs often show variable or partial TSDR demethylation, indicating greater plasticity. Stabilization strategies include using TGF-β in combination with IL-2 and, in some contexts, agents such as ATRA or rapamycin.

Clinical relevance and research focus on iTregs include potential applications in autoimmune disease, transplantation tolerance, graft-versus-host disease, and allergy. Key challenges are achieving durable Foxp3 expression and suppressive function in vivo and preventing conversion to pro-inflammatory phenotypes in inflammatory environments.