PD-L1 regulates the development, maintenance, and function of induced regulatory T cells

By Loise M. Francisco, Victor H. Salinas, Keturah E. Brown, V. Vanguri, G. Freeman, V. Kuchroo, Arlene H. Sharpe. Journal of Experimental Medicine, 2009

2,028 citations recorded by the source corpus.

Both the programmed death (PD) 1–PD-ligand (PD-L) pathway and regulatory T (T reg) cells are instrumental to the maintenance of peripheral tolerance. We demonstrate that PD-L1 has a pivotal role in regulating induced T reg (iT reg) cell development and sustaining iT reg cell function. PD-L1−/− antigen-presenting cells minimally convert naive CD4 T cells to iT reg cells, showing the essential role of PD-L1 for iT reg cell induction. PD-L1–coated beads induce iT reg cells in vitro, indicating that PD-L1 itself regulates iT reg cell development. Furthermore, PD-L1 enhances and sustains Foxp3 expression and the suppressive function of iT reg cells. The obligatory role for PD-L1 in controlling iT reg cell development and function in vivo is illustrated by a marked reduction in iT reg cell conversion and rapid onset of a fatal inflammatory phenotype in PD-L1−/−PD-L2−/− Rag−/− recipients of naive CD4 T cells. PD-L1 iT reg cell development is mediated through the down-regulation of phospho-Akt, mTOR, S6, and ERK2 and concomitant with the up-regulation of PTEN, all key signaling molecules which are critical for iT reg cell development. Thus, PD-L1 can inhibit T cell responses by promoting both the induction and maintenance of iT reg cells. These studies define a novel mechanism for iT reg cell development and function, as well as a new strategy for controlling T reg cell plasticity.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/b23143756625e53a284a972c3605ce367ff17b9f

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In Immunology

1. D. Pardoll
2. Lieping Chen
3. Arlene H. Sharpe
4. G. Freeman
5. S. Topalian
6. Charles G. Drake
7. Xue Han
8. G. Dranoff

Citations in the corpus

• Combination of CTLA-4 and PD-1 blockers for treatment of cancer (2019, background): “types of cancers including bladder, lung, colon, breast, kidney, ovary, cervix, melanoma, glioblastoma, multiple myeloma and T-cell lymphoma [41, 43].”
• Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. (2014, positive): “cytokine stimulation, 4 × 105 Gr1+ cells were stimulated for 21 hours with either the promotion of Treg development or the reversal of their suppressive function (39, 40).”
• Metabolic Regulation of Immune Responses (2014, background): “Ligation of the inhibitory receptors PD-1 and CTLA-4, which inhibit T cell activation, prevented PI3K/Akt activation and the switch to glycolytic metabolism (91, 94, 95).”
• Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2 (2012, result): “In contrast to these in vitro studies of exhausted T cells, PD-1 expressed on T reg cells seems to exhibit distinct functions in vivo because a PD-L1–Ig chimeric protein can induce a profound increase of T reg cells by enhancement of Foxp3 expression (Francisco et al., 2009).”
• Dual Blockade of PD-1 and CTLA-4 Combined with Tumor Vaccine Effectively Restores T Cell Rejection Function in Tumors (2013, background): “The importance of the PD-1 pathway for Tregs, however, is not well characterized, although one recent study described PD-L1 expression by Tregs (36).”
• PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity (2017, background): “Early mechanistic studies of the PD-1 pathway showed that PD-1 ligation can inhibit the initial activation of T cells and suppress effector T cell generation and function, including cytokine production and cytotoxicity (Hirano et al., 2005; Francisco et al., 2009).”
• Metabolic Regulation of T Lymphocytes (2013, background): “Similarly, ligation of PD-1 can inhibit both mTORC1 and mTORC2 signaling, thus diminishing glycolytic metabolism within the target cell (108).”
• Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors (2013, result): “Although previous studies have shown that PD-L1 induces regulatory T cells (22), PD-1 blockade did not change the numbers of regulatory T cells (Fig 3c).”
• CTLA-4 and PD-1 Pathways (2016, result): “PD-L1 has been shown to contribute to the conversion of naive CD4 + T cells to Treg cells34 and to inhibit T-cell responses by promoting the induction and maintenance of Tregs.35 Consistent with these findings, PD-1 blockade can reverse Tregmediated suppression of effector T cells in vitro.36 PD-1 b”
• Treg cells expressing the co-inhibitory molecule TIGIT selectively inhibit pro-inflammatory Th1 and Th17 cell responses (2014, background): “PD-1 plays an important role in iTreg cell stability and suppressive function (Francisco et al., 2009).”
• PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy (2015, background): “In PD1 and PD-L1 knockout mice, the autoimmune phenotype is milder as compared to that in CTLA-4 knockouts (10, 11).”