The Proteomic Landscape of Human Ex Vivo Regulatory and Conventional T Cells Reveals Specific Metabolic Requirements

Claudio Procaccini, Fortunata Carbone, Dario Di Silvestre, Francesca Brambilla, Veronica De Rosa, Mario Galgani, Deriggio Faicchia, Gianni Marone, Donatella Tramontano, Marco Corona, Carlo Alviggi, Antonio Porcellini, Antonio La Cava, Pierluigi Mauri, Giuseppe Matarese, Claudio Procaccini, Fortunata Carbone, Dario Di Silvestre, Francesca Brambilla, Veronica De Rosa, Mario Galgani, Deriggio Faicchia, Gianni Marone, Donatella Tramontano, Marco Corona, Carlo Alviggi, Antonio Porcellini, Antonio La Cava, Pierluigi Mauri, Giuseppe Matarese

Abstract

Human CD4(+)CD25(hi)Foxp3(+)CD127(-) Treg and CD4(+)CD25(-)Foxp3(-) Tconv cell functions are governed by their metabolic requirements. Here we report a comprehensive comparative analysis between ex vivo human Treg and Tconv cells that comprises analyses of the proteomic networks in subcellular compartments. We identified a dominant proteomic signature at the metabolic level that primarily impacted the highly-tuned balance between glucose and fatty-acid oxidation in the two cell types. Ex vivo Treg cells were highly glycolytic while Tconv cells used predominantly fatty-acid oxidation (FAO). When cultured in vitro, Treg cells engaged both glycolysis and FAO to proliferate, while Tconv cell proliferation mainly relied on glucose metabolism. Our unbiased proteomic analysis provides a molecular picture of the impact of metabolism on ex vivo human Treg versus Tconv cell functions that might be relevant for therapeutic manipulations of these cells.

Keywords: Conventional T cells; Immune Tolerance; Metabolism; Proteomic Analysis; Regulatory T cells.

Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Freshly-Isolated Human Treg Cells Display a Glycolytic Metabolism whereas Tconv Cells Preferentially Use FAO (A and B) Map of the interactome networks controlling the main biological processes/functions associated to metabolism (mitochondrial proteins, ribosome, lipid metabolism and glycolysis), obtained by comparing the protein profile of freshly-isolated Tconv and Treg cells in the membranes (A) and in the cytoplasm (B). Red plots correspond to specific proteins upregulated in Treg cells; blue plots correspond to proteins upregulated in Tconv cells; pink plots represent the equally distributed proteins in the two cell compartments; white plots are the not-identified proteins. (C) Left, representative flow cytometry plots (percentage of Ki67+ cells indicated above the boxes) from freshly-isolated Tconv and Treg cells (SSC, side scatter) (one representative plot out of ten). Right shows percentage of Ki67+ cells from freshly-isolated Tconv and Treg cells. The data are shown as mean ± SEM of ten independent experiments. (D and E) ECAR in basal condition (D) and upon glucose injection (E) on freshly-isolated Tconv and Treg cells (one representative out of three independent experiments). The data are shown as mean ± SEM of three measurements, each of them in duplicates. (F) OCR in freshly-isolated Tconv and Treg cells (one representative out of three independent experiments). The data are shown as mean ± SEM of three measurements, each of them in duplicates. (G) Percentage of FAO in freshly-isolated Tconv and Treg cells (one representative out of three independent experiments). The data are shown as mean ± SEM of three measurements, each of them in triplicates. (C–G) Statistical analysis by two tailed Mann-Whitney test. (∗p < 0.05; ∗∗p < 0.005, ∗∗∗p < 0.0005). (H and I) Immunoblot for aldolase, enolase, hexokinase, PKM1/2, FAS, ApoA4, HADHA, ACAD9, DLST, and SDHA on freshly-isolated Tconv and Treg cells. Actin and total ERK 1/2 served as a loading control. One representative out of at least two independent experiments is shown. The graphs show the relative densitometric quantitation of aldolase, hexokinase, PKM1/2, enolase, FAS, ApoA4, HADHA, ACAD9, DLST, and SDHA normalized on actin in freshly-isolated Tconv and Treg cells and shown as fold over Tconv cells (n = 6; data are shown as mean ± SEM of two independent experiments, in triplicates). (H–I) Statistical analysis by paired two-tailed Student’s t test (∗p < 0.05, ∗∗p < 0.001, ∗∗∗p < 0.0001).
Figure 2
Figure 2
Proteomic and Metabolic Profiles of In Vitro Anergic and Proliferating Human Treg Cells Maps of the interactome networks controlling the main biological processes/functional classes associated to metabolism, obtained by comparing unstimulated Treg cells with in vitro cultured Treg cells stimulated with anti-CD3 and anti-CD28 in the membranes (A) and in the cytosol (B), and by comparing anti-CD3 and anti-CD28-stimulated Treg cells with leptin-neutralized Treg cells, in the membranes (C) and in the cytosol (D). Red plots correspond to specific proteins upregulated in anti-CD3 and anti-CD28-stimulated Treg cells; blue plots correspond to proteins downregulated in anti-CD3 and anti-CD28-stimulated Treg cells (A and B) and to proteins upregulated in leptin-neutralized-Treg cells (C) and (D); pink plots represent the equally distributed proteins in the two experimental conditions; white plots are the not-identified proteins.
Figure 3
Figure 3
Human Treg Cell Proliferation In Vitro Requires Both Glycolysis and FAO (A) In vitro proliferation of Treg cells upon 72 hr anti-CD3 and anti-CD28 stimulation in the presence or absence of leptin-neutralizing antibody. The data are shown as mean ± SEM (n = 6). (B) Immunoblot for P-ERK1/2 on human Treg cells upon 12 hr anti-CD3 and anti-CD28 stimulation in the presence or absence of leptin-neutralizing antibody. Total ERK1/2 served as a loading control. One representative out of three independent experiments is shown. (C) In vitro proliferation of Treg cells upon 72 hr anti-CD3 and anti-CD28 stimulation in the presence or absence of leptin-neutralizing antibody, 2-DG, or Etomoxir, alone or in combination. The data are shown as mean ± SEM (n = 3). (D) Fold inhibition of Treg cell proliferation upon leptin neutralization in the presence of 2-DG or Etomoxir. The data are shown as mean ± SEM (n = 3). (E) Kinetic profile of ECAR in Treg cells stimulated or not with anti-CD3 and anti-CD28 for 12 hr, in the presence or absence of leptin-neutralizing antibody (one representative out of three independent experiments). The data are shown as mean ± SEM of duplicates. ECAR was measured in real time, under basal conditions and in response to glucose, oligomycin and 2-DG. Indices of glycolytic pathway activation, calculated from Treg cells ECAR profile: basal ECAR (F), maximal ECAR (G), and glycolytic capacity (H) in Treg cells stimulated or not with anti-CD3 and anti-CD28 for 12 hr, in the presence or absence of leptin-neutralizing antibody (one representative out of three independent experiments). Data are expressed as mean ± SEM of three measurements, each of them in duplicates. (I) ECAR profile of unstimulated Treg cells before and after leptin-neutralizing antibody injection (one representative out of three independent experiments). The data are shown as mean ± SEM of triplicates. (J) Kinetic profile of OCR in Treg cells stimulated or not with anti-CD3 and anti-CD28 for 12 hr, in the presence or absence of leptin-neutralizing antibody (one representative out of three independent experiments). The data are shown as mean ± SEM of duplicates. OCR was measured in real time, under basal conditions and in response to indicated mitochondrial inhibitors: oligomycin, FCCP, Antimycin A and Rotenone. Indices of mitochondrial respiratory function, calculated from Treg cells OCR profile: basal OCR (K), ATP-linked OCR (L), and maximal OCR (M) in Treg cells stimulated or not with anti-CD3 and anti-CD28 for 12 hr, in the presence or absence of leptin-neutralizing antibody (one representative out of three independent experiments). Data are expressed as mean ± SEM of three measurements, each of them in duplicates. (N and O) Percentage of FAO in Treg cells stimulated or not with anti-CD3 and anti-CD28 for 12 hr in the presence or absence of leptin-neutralizing antibody. FAO was evaluated in basal conditions (N) and during maximal respiration (O) (one representative out of three independent experiments). Data are expressed as mean ± SEM of three measurements, each of them in duplicates. (P) Immunoblot for aldolase, enolase, hexokinase, and PKM1/2, FAS, ApoA4, HADHA, ACAD9, CPT1A, on Treg cells upon 12 hr anti-CD3 and anti-CD28 stimulation in the presence or absence of leptin-neutralizing antibody. Actin and total ERK 1/2 served as a loading control. One representative out of two independent experiments is shown. The graphs show the relative densitometric quantitation of aldolase, enolase, hexokinase, PKM1/2, FAS, ApoA4, HADHA, ACAD9, and CPT1A normalized on actin in unstimulated (white columns), anti-CD3, and anti-CD28-stimulated (gray columns) and leptin-neutralized Treg cells (black columns) and shown as fold over unstimulated Treg cells (n = 6; data are shown as mean ± SEM of at least two independent experiments, in triplicates). All statistical analysis by paired two-tailed Student’s t test. (∗p < 0.05, ∗∗p < 0.001, ∗∗∗p < 0.0001).
Figure 4
Figure 4
Suppressive Function of Human Treg Cells Requires Both Glycolysis and FAO (A) Representative flow cytometry plots showing expression of lineage specific markers (CTLA-4, PD-1, CD25) in Treg cells upon 12 hr pretreatment with vehicle (CTR), 2-DG, or etomoxir. Percentage and MFI of positive cells are indicated. One representative out of three independent experiments is shown. (B) Percentage of inhibition of CFSE-labeled Tconv cell proliferation co-cultured for 72 hr with Treg cells pre-treated 12 hr with vehicle, 2-DG, or etomoxir. The data are shown as mean ± SEM and are expressed as reduction over CTR (n = 8). (C) Immunoblot for FoxP3, actin, total ERK1/2, P-STAT5, STAT5, P-S6, and S6 on Treg cells upon 12 hr anti-CD3 and anti-CD28 stimulation in the presence or absence of 2-DG or etomoxir. One representative out of two independent experiments is shown. The graphs show the relative densitometric quantitation of FoxP3 (normalized on actin and total ERK 1/2), P-STAT5 (normalized on total STAT5), and P-S6 (normalized on total S6) (n = 6, data are shown as mean ± SEM of two independent experiments, in triplicates). All statistical analysis by paired two-tailed Student’s t test (∗p < 0.05, ∗∗p < 0.005).
Figure 5
Figure 5
Proteomic and metabolic profiles of in vitro-cultured human Tconv cells Maps of the interactome networks controlling the main biological processes/functional classes associated to metabolism, obtained by comparing unstimulated Tconv cells with in vitro cultured Tconv cells stimulated with anti-CD3 and anti-CD28 in the membranes (A) and in the cytosol (B), and by comparing anti-CD3 and anti-CD28-stimulated Tconv cells with leptin-neutralized Tconv cells, in the membranes (C) and in the cytosol (D). Red plots correspond to specific proteins upregulated in anti-CD3 and anti-CD28-stimulated Tconv cells; blue plots correspond to proteins downregulated in anti-CD3 and anti-CD28-stimulated Tconv cells (A) and (B) and to proteins upregulated in leptin-neutralized Tconv cells (C) and (D); pink plots represent the equally distributed proteins in the two experimental conditions; white plots are the not-identified proteins.
Figure 6
Figure 6
Human Tconv Cell Proliferation In Vitro Requires Glycolysis but Not FAO (A) In vitro proliferation of Tconv cells upon 72 hr anti-CD3 and anti-CD28 stimulation in the presence or absence of leptin-neutralizing antibody. The data are shown as mean ± SEM (n = 6). (B) Immunoblot for P-ERK1/2 on human Tconv cells upon 12 hr anti-CD3 and anti-CD28 stimulation in the presence or absence of leptin-neutralizing antibody. Total ERK1/2 served as a loading control. One representative out of three independent experiments is shown. (C) In vitro proliferation of Tconv cells upon 72 hr anti-CD3 and anti-CD28 stimulation in the presence or absence of leptin-neutralizing antibody, 2-DG, or etomoxir, alone or in combination. The data are shown as mean ± SEM (n = 3). (D) Fold inhibition in Tconv cells proliferation upon TCR-mediated stimulation in the presence of 2-DG and etomoxir. The data are shown as mean ± SEM (n = 3). (E) Kinetic profile of ECAR in Tconv cells stimulated or not with anti-CD3 and anti-CD28 for 12 hr, in the presence or absence of leptin-neutralizing antibody (one representative out of three independent experiments). The data are shown as mean ± SEM of triplicates. ECAR was measured in real time, under basal conditions and in response to glucose, oligomycin, and 2-DG. Indices of glycolytic pathway activation, calculated from Tconv ECAR profile: basal ECAR (F), maximal ECAR (G), and glycolytic capacity (H) in Tconv cells stimulated or not with anti-CD3 and anti-CD28 for 12 hr, in the presence or absence of leptin-neutralizing antibody (one representative out of three independent experiments). Data are expressed as mean ± SEM of three measurements, each of them in triplicates. (I) Kinetic profile of OCR in Tconv cells stimulated or not with anti-CD3 and anti-CD28 for 12 hr, in the presence or absence of leptin-neutralizing antibody (one representative out of three independent experiments). The data are shown as mean ± SEM of triplicates. OCR was measured in real time, under basal conditions and in response to indicated mitochondrial inhibitors: oligomycin, FCCP, Antimycin A, and Rotenone. Indices of mitochondrial respiratory function, calculated from Tconv OCR profile: basal OCR (J), ATP-linked OCR (K), maximal OCR (L) in Tconv cells stimulated or not with anti-CD3 and anti-CD28 for 12 hr, in the presence or absence of leptin-neutralizing antibody (one representative out of three independent experiments). Data are expressed as mean ± SEM of three measurements, each of them in triplicates. (M and N) Percentage of FAO in Tconv cells stimulated or not with anti-CD3 and anti-CD28 for 12 hr in the presence or absence of leptin-neutralizing antibody. FAO was evaluated in basal conditions (M) and during maximal respiration (N) (one representative out of three independent experiments). Data are expressed as mean ± SEM of three measurements, each of them in duplicates. (O) Immunoblot for Aldolase, Enolase, Hexokinase, and PKM1/2, Fatty acid synthase (FAS), ApoA4, HADHA, ACAD9, CPT1A on Tconv cells upon 12 hr anti-CD3, and anti-CD28 stimulation in the presence or absence of leptin-neutralizing antibody. Actin and total ERK 1/2 served as a loading control. One representative out of three independent experiments is shown. The graphs show the relative densitometric quantitation of Aldolase, Enolase, Hexokinase, PKM1/2, FAS, ApoA4, HADHA, ACAD9, and CPT1A normalized on actin in unstimulated (white columns), anti-CD3 and anti-CD28-stimulated (gray columns), and leptin-neutralized Tconv cells (black columms) and shown as fold over unstimulated Tconv cells. (n = 6; data are shown as mean ± SEM of two independent experiments, in triplicates). All statistical analysis by paired two-tailed Student’s t test. (∗p < 0.05, ∗∗p < 0.001, ∗∗∗p < 0.0001).
Figure 7
Figure 7
Effector Functions of Human Tconv Cells Are Mainly Sustained by Glycolysis (A) Representative flow cytometry plots showing expression of activation markers (CD25, CD127, CD71, ICAM-1, VLA-4, and CTLA-4) in Tconv cells upon 36 hr activation with anti-CD3 and anti-CD28 in the presence or absence of 2-DG or etomoxir. Percentage and MFI of positive cells are indicated. One representative out of two independent experiments is shown. (B) MFI of IL-2 and IFN-γ expression in Tconv cells stimulated for 12 hr with anti-CD3 and anti-CD28 in the presence or absence of 2-DG or etomoxir, analyzed by flow cytometry. Data are expressed as mean ± SEM (n = 3). (C) Immunoblot for P-ERK 1/2, P-STAT5, and P-S6 on Tconv cells upon 12 hr anti-CD3 and anti-CD28 stimulation in the presence or absence of 2-DG or etomoxir. Total ERK 1/2, total STAT5, and total S6 served as a loading control. One representative out of two independent experiments is shown. The graphs show the relative densitometric quantitation of each phosphorylated protein normalized on its total form, in Tconv cells treated for 12 hr with anti-CD3 and anti-CD28 in the presence or absence of 2-DG or etomoxir (n = 6, data are shown as mean ± SEM of two independent experiments, in triplicates). All statistical analysis by paired two-tailed Student’s t test (∗p < 0.05, ∗∗p < 0.005).

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