The PDL1-PD1 Axis Converts Human T _H 1 Cells into Regulatory T Cells

Abstract

Immune surveillance by T helper type 1 (Th1) cells is critical for the host response to tumors and infection, but also contributes to autoimmunity and graft-versus-host disease (GvHD) after transplantation. The inhibitory molecule programmed death ligand-1 (PDL1) has been shown to anergize human Th1 cells, but other mechanisms of PDL1-mediated Th1 inhibition such as the conversion of Th1 cells to a regulatory phenotype have not been well characterized. We hypothesized that PDL1 may cause Th1 cells to manifest differentiation plasticity. Conventional T cells or irradiated K562 myeloid tumor cells overexpressing PDL1 converted TBET+ Th1 cells into FOXP3+ regulatory T cells (TREGS) in vivo, thereby preventing human-into-mouse xenogeneic GvHD (xGvHD). Either blocking PD1 expression on Th1 cells by siRNA targeting or abrogation of PD1 signaling by SHP1/2 pharmacologic inhibition stabilized Th1 cell differentiation during PDL1 challenge and restored the capacity of Th1 cells to mediate lethal xGVHD. PD1 signaling therefore induces human Th1 cells to manifest in vivo plasticity, resulting in a TREG phenotype that severely impairs cell-mediated immunity. Converting human Th1 cells to a regulatory phenotype with PD1 signaling provides a potential way to block GvHD after transplantation. Moreover, because this conversion can be prevented by blocking PD1 expression or pharmacologically inhibiting SHP1/2, this pathway provides a new therapeutic direction for enhancing T cell immunity to cancer and infection.

Anti–IL-7 receptor-α reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function

“…A recent report showed that PD-1/PD-L1 signaling converts human T H 1 cells into Tregs in vitro and in vivo, thereby preventing human-into-mouse xenogeneic graft-vs.-host disease. Recipient of T H 1 cells plus T cells expressing PD-L1 had a reduced number of T-bet + T cells and an increased number of Foxp3 + T cells (43). In this connection, we also noted an increased frequency and also absolute number of Tregs in certainbut not all-lymphoid compartments in NOD mice treated with IL-7Rα antibody.…”

Fatal GvHD induced by PD-1 inhibitor pembrolizumab in a patient with Hodgkin’s lymphoma

“…This provides an additional mechanism of how PD-1 blockade could cause worsening GvHD mortality. Amarnath et al 19 showed that PD-L1 caused human Th1 cells to convert into T reg cells both in vitro and in vivo resulting in inhibition of GvHD. In this experiment, restoration of GvHD was achieved by blocking PD-1 or by pharmacological inhibition of SHP1/SHP2, which are signaling molecules downstream to PD-1 receptor.…”

Role of PD1/PDL1 pathway, and TH17 and treg cells in maternal tolerance to the fetus

“…It is already known that the PD1/PDL1 pathway is involved in the con-version of Th1 cells to Tregs. [78] Figure 1 depicts possible mechanism of PD1-PDL1 induced tolerance at the FMI.…”

“…[78] The PD1/PDL1 pathway is also thought to maintain peripheral tolerance. [45] The role of this pathway is relevant in the context of feto-maternal tolerance, as PDL1 is expressed on the trophoblast cells of the placenta and PD1 is expressed on the maternal effector and Tregs.…”