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

Loise M Francisco, Victor H Salinas, Keturah E Brown, Vijay K Vanguri, Gordon J Freeman, Vijay K Kuchroo, Arlene H Sharpe, Loise M Francisco, Victor H Salinas, Keturah E Brown, Vijay K Vanguri, Gordon J Freeman, Vijay K Kuchroo, Arlene H Sharpe

Abstract

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.

Figures

Figure 1.
Figure 1.
PD-L1 mediates Foxp3+ iT reg cell development. (A and B) Development of Foxp3+ iT reg cells was assessed by flow cytometric analysis of Foxp3-GFP expression after co-culture of naive CD4+CD62L+Foxp3.GFP− T cells with anti-CD3 and irradiated WT or PD-L1−/− APCs plus the indicated range of TGF-β concentrations for 3 d (A) or PD-L1–Ig or control Ig (human IgG1)–coupled beads (B). One representative experiment of at least three similar experiments is shown. (C) Analysis of Foxp3-GFP expression after culture of naive CD4+CD62L+Foxp3.GFP− T cells with PD-L1–Ig beads and over the indicated range of TGF-β concentrations. *, P < 0.001 for PD-L1 bead comparing 0 ng/ml TGF-β versus 0.5–8 ng/ml; **, P < 0.001 comparing PD-L1 bead versus control bead at 0.5 ng/ml TGF-β. Data represent the mean ± SD and are representative of at least four independent experiments. (D) Naive CD4 T cells were cultured in the presence of control Ig or PD-L1–Ig beads (with increasing amounts of PD-L1) in the presence of low levels of TGF-β. *, P = 0.05; **, P = 0.0006; ***, P < 0.0001. Data are representative of three similar experiments. (E) Analysis of CFSE dye dilution of naive CD4+CD62L+CD25− CD44low 2D2 Tg T cells cultured with increasing quantities of PD-L1–Ig (PD-L1 bead is coated with anti-CD3, anti-CD28, and 20, 40, or 60% PD-L1–Ig, respectively) or control Ig in the presence of TGF-β. After 3 d of co-culture, cells were stained for Foxp3 expression. 20 U/ml of exogenous IL-2 was added to cultures shown on the bottom (green). Data are representative of three similar experiments. (F) Quantitative analysis of Foxp3+ T cell conversion in the presence or absence of IL-2 and increasing quantities of immobilized PD-L1. *, P < 0.0001 for all concentrations of PD-L1–Ig versus control Ig in the absence of IL-2; *, P = 0.005 and **, P = 0.0021 for 40 and 60% PD-L1–Ig, respectively, versus control Ig, in the presence of IL-2. Data are representative of three similar experiments. (G) Analysis of Foxp3 expression on a per cell basis, quantified via MFI. *, P = 0.0003 and **, P < 0.001, PD-L1–Ig 20% and PD-L1–Ig 40% versus control Ig, in the absence of IL-2; *, P = 0.03, PD-L1–Ig 60 versus control Ig, in presence of IL-2. Data represent the mean ± SD and are representative of more than five independent experiments with n = 3 mice per treatment condition.
Figure 2.
Figure 2.
PD-L1–induced CD4+ Foxp3+ T reg cells suppress CD4+ T eff cells in vitro. (A) PD-L1 iT reg cell function was assessed by [3H]thymidine incorporation of naive CD4+CD25− T eff cells after 3 d of co-culture at a 1:1 T reg/T eff cell ratio plus PD-L1 beads (5:1 bead/T eff cell ratio). Data represent the mean ± SD and are representative of at least two independent experiments. (B) PD-L1 iT reg cell function was assessed by CFSE dilution of naive CD4+CD25− T eff cells after 3 d of incubation with 1:1 T reg/T eff cell ratio and PD-L1 beads (5:1 bead/T eff cell ratio). Data represent the mean ± SD and are representative of three similar experiments. (C) Quantification of T eff cell proliferation in B, analyzing the division index of gated CD4+CD45.1+ (the number of divisions a single cell has divided) by FlowJo software. Data represent the mean ± SD.
Figure 3.
Figure 3.
PD-L1 maintains Foxp3 expression by iT reg cells during suppression of effector cell function. (A) Schematic depiction of experiment. Naive CD4+CD62LhiFoxp3.GFP− T cells were induced toward T reg cell differentiation for 3 d in the presence of TGF-β plus IL-2 and either control or PD-L1 beads. Foxp3.GFP+CD45.1− cells were then sorted and co-cultured with sorted CD4+CD25−CD45.1+ in the presence of either control or PD-L1 beads during the 3-d suppression assay. (B) 72 h after co-culture, CD4+CD45.1− cells were gated and analyzed for GFP expression. (C) Quantification of experiment depicted in B. Data represent the mean ± SD and are representative of at least two independent experiments.
Figure 4.
Figure 4.
PD-L1 enhances the efficiency of iT reg cell–mediated suppression of T eff cells. (A) Foxp3.GFP+ iT reg cells were sorted and co-cultured with naive CD4+CD25−CD45.1+ T eff cells plus either PD-L1–Ig beads or control Ig beads (at various T reg/T eff cell ratios). 72 h later, cultures were pulsed with [3H]thymidine for 12–14 h. P < 0.0009 at a 1:4 ratio cultured with PD-L1 beads (comparing T eff + iT reg vs. T eff cells). Data represent the mean proliferation ± SD and are representative of at least four independent experiments. (B) Quantification of suppression at 1:4 ratio of T reg/T eff cells. P = 0.0149. Data represent the mean ± SD and are representative of at least four independent experiments. (C) PD-L1 iT reg cells suppress T eff cells more effectively than control iT reg cells. CD4+CD62L+ FoxP3.GFP− naive T cells were induced with PD-L1 or control beads in the presence of TGF-β. GFP+ iT reg cells were sorted and co-cultured at the indicated T reg/T eff cell ratios with CFSE-labeled CD4+CD25− Thy1.1 T eff cells and beads coated with anti-CD3 and anti-CD28 (in the absence of PD-L1) for 3 d. Graphs are representative of three experimental replicates and data are representative of three independent experiments.
Figure 5.
Figure 5.
Attenuated iT reg cell development in PD-L1−/−PD-L2−/− mice in vivo. (A) CD4+CD62LhiFoxp3.GFP− cells were adoptively transferred i.v. into the tail veins of WT Rag−/− or PD-L1−/−PD-L2−/−Rag−/− mice. Spleens and lymph nodes were analyzed for Foxp3.GFP expression 14–17 d after transfer. (B) Quantitation of Foxp3.GFP expression from independent mice depicted in A. Data represent the mean ± SE of five independent mice. (C and D) Analysis of IL-17+ and IFN-γ+ T eff cells by intracellular cytokine staining (C) and ratios of IL-17–producing T eff/T reg cells and IFN-γ–producing T eff/T reg cells from WT Rag−/− or PD-L1−/−PD-L2−/−Rag−/− mice 14–17 d after transfer (D). Data represent the mean ± SD of n = 5 mice per group and are representative of two independent experiments.
Figure 6.
Figure 6.
Dramatic weight loss, severe pulmonary inflammation, and fatal inflammatory disorder develop in PD-L1−/−PD-L2−/− Rag−/− mice after adoptive transfer of naive CD4+CD62LhiFoxp3.GFP− T cells. Sorted CD4+CD62LhiFoxp3.GFP− cells were adoptively transferred i.v. into WT Rag−/− or PD-L1−/−PD-L2−/− Rag−/− mice. (A and B) Clinical manifestations shown are the following: percentage of weight loss of mice after adoptive transfer of CD4+CD62LhiFoxp3.GFP− cells into WT Rag−/− or PD-L1−/−PD-L2−/−Rag−/− (P < 0.001; n = 5 mice per group; A) and quantified lymph node (axillary, brachial, and inguinal) cellularity (B). Data represent the mean ± SD and represent two independent experiments. (C) Survival of mice after adoptive transfer of naive CD4+CD62LhiFoxp3.GFP− T cells was monitored for 30 d. PD-L1−/−PD-L2−/− Rag−/−, n = 12; WT Rag−/−, n = 8. (D) Hematoxylin and eosin–stained paraffin sections of lung tissue obtained on days 14–17 after transfer of naive CD4+CD62LhiFoxp3− T cells. Bars: (top, 40×) 500 µm; (bottom, 400×) 50 µm. PD-L1−/−PD-L2−/− Rag−/−, n = 9; WT Rag−/−, n = 10. Data represent more than four independent experiments.
Figure 7.
Figure 7.
PD-L1 regulates T reg cell development by antagonizing the Akt–mTOR signaling cascade. (A, C, F, and G) Phospho-Akt, phospho-mTOR, PTEN, and phospho-S6 analysis at 18 h after culture with control Ig bead (hIgG = 60% of bead surface, with remaining surface coated with anti-CD3 and anti-CD28) or various titers of PD-L1–Ig bead (PD-L1–Ig 20, 40, 60 = 20, 40, and 60% of bead surface coated with PD-L1–Ig, with remaining surface coated with anti-CD3 and anti-CD28 plus control Ig). (B, D, E, and G) MFI analysis of phospho-Akt (B; *, P = 0.001; **, P = 0.003; and ***, P = 0.0008, at 20, 40, and 60% PD-L1, respectively, compared with control Ig), phospho-mTOR (D; *, P = 0.0064; and **, P = 0.0001, at 20 and 60% PD-L1, respectively, compared with control Ig), phospho-S6 (E; P = 0.0012, P = 0.0007, and P = 0.0002, at 20, 40, and 60% PD-L1, respectively, compared with control Ig), and PTEN (H; *, P = 0.0378, PD-L1–Ig 40 compared with control Ig) at 18 h. n = 3 mice per experiment, representative of three experiments. Data are representative of the MFI ± SD and are representative of three experiments.

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