LAG-3⁺ Regulatory T Cells Suppress Effector Function of T Cells and Allow Their Proliferation Into Regulatory T Cells

LAG-3⁺ regulatory T cells suppress the effector but not the proliferative response of naïve cognate antigen-specific CD4⁺ T cells in vivo. The Th1, Th2, and Th17 machineries in the suppressed CD4⁺ T cells are impaired. Genomic study of the suppressed T cells revealed enhanced T cell receptor signalling with up-regulation of immune checkpoints, including PD-1 and PD-L1, and down-regulation of pro-inflammatory pathways. Although oxidative metabolism is reduced, the suppressed T cells retain proliferative capacity and acquire LAG-3 expression with proliferation. They acquire the capacity of LAG-3⁺ regulatory T cells. They inhibit the IFN-γ response of co-cultured naïve CD4⁺ T cells in vitro. Upon adoptive transfer, they rescue mice from lethal autoimmune pulmonitis in a dose-dependent manner. Our results implied a mechanism for the maintenance of long-lasting antigen-specific tolerance.