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.