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In vitro  induced human regulatory T cells (iTregs) have demonstrated  in vivo  therapeutic utility, but pathways regulating their function have not been elucidated. Here, we report that human iTregs generated  in vitro  from naïve cord blood cells preferentially recruit Disc large homolog 1 (Dlgh1) and exclude protein kinase C (PKC)-θ from immunological synapses formed on supported lipid bilayers with laterally mobile ICAM-1 and anti-CD3 mAb. Also, iTregs display elevated Dlgh1 overall and Dlgh1-dependent p38 phosphorylation, higher levels of phosphatase and tensin homolog (PTEN), and diminished Akt phosphorylation. Pharmacological interruption of PKC-θ increases and Dlgh1 silencing decreases the ability of iTregs to suppress interferon-γ production by CD4 + CD25 −  effector T cells (Teff). Comparison with expanded cord blood-derived CD4 + CD25 hi  tTreg and expanded Teffs from the same donors indicate that iTreg are intermediate between expanded CD4 + CD25 hi  tTregs and Teffs, whereas modulation of suppressive activities by PKC-θ and Dlgh1 signaling pathways are shared.

Human in vitro-induced regulatory T cells display Dlgh1 dependent and PKC-θ restrained suppressive activity