Inherent metabolic preferences differentially regulate the sensitivity of Th1 and Th2 cells to ribosome-inhibiting antibiotics
Neha Jawla
Molecular Genetics Laboratory, National Institute of Immunology, New Delhi, India
Search for more papers by this authorRaunak Kar
Immuno Genomics Laboratory, National Institute of Immunology, New Delhi, India
Search for more papers by this authorVeena S. Patil
Immuno Genomics Laboratory, National Institute of Immunology, New Delhi, India
Search for more papers by this authorCorresponding Author
G. Aneeshkumar Arimbasseri
Molecular Genetics Laboratory, National Institute of Immunology, New Delhi, India
Correspondence
G. Aneeshkumar Arimbasseri, Molecular Genetics Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg 110067, New Delhi.
Email: [email protected]
Search for more papers by this authorNeha Jawla
Molecular Genetics Laboratory, National Institute of Immunology, New Delhi, India
Search for more papers by this authorRaunak Kar
Immuno Genomics Laboratory, National Institute of Immunology, New Delhi, India
Search for more papers by this authorVeena S. Patil
Immuno Genomics Laboratory, National Institute of Immunology, New Delhi, India
Search for more papers by this authorCorresponding Author
G. Aneeshkumar Arimbasseri
Molecular Genetics Laboratory, National Institute of Immunology, New Delhi, India
Correspondence
G. Aneeshkumar Arimbasseri, Molecular Genetics Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg 110067, New Delhi.
Email: [email protected]
Search for more papers by this authorAbstract
Mitochondrial translation is essential to maintain mitochondrial function and energy production. Mutations in genes associated with mitochondrial translation cause several developmental disorders, and immune dysfunction is observed in many such patients. Besides genetic mutations, several antibiotics targeting bacterial ribosomes are well-established to inhibit mitochondrial translation. However, the effect of such antibiotics on different immune cells is not fully understood. Here, we addressed the differential effect of mitochondrial translation inhibition on different subsets of helper T cells (Th) of mice and humans. Inhibition of mitochondrial translation reduced the levels of mitochondrially encoded electron transport chain subunits without affecting their nuclear-encoded counterparts. As a result, mitochondrial oxygen consumption reduced dramatically, but mitochondrial mass was unaffected. Most importantly, we show that inhibition of mitochondrial translation induced apoptosis, specifically in Th2 cells. This increase in apoptosis was associated with higher expression of Bim and Puma, two activators of the intrinsic pathway of apoptosis. We propose that this difference in the sensitivity of Th1 and Th2 cells to mitochondrial translation inhibition reflects the intrinsic metabolic demands of these subtypes. Though Th1 and Th2 cells exhibit similar levels of oxidative phosphorylation, Th1 cells exhibit higher levels of aerobic glycolysis than Th2 cells. Moreover, Th1 cells are more sensitive to the inhibition of glycolysis, while higher concentrations of glycolysis inhibitor 2-deoxyglucose are required to induce cell death in the Th2 lineage. These observations reveal that selection of metabolic pathways for substrate utilization during differentiation of Th1 and Th2 lineages is a fundamental process conserved across species.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| imm13860-sup-0001-FigureS1.pdfPDF document, 954.6 KB | Figure S1. Chloramphenicol inhibits mitochondrial ETC. (A) Representative FACS plot showing the expression of CD44 and CD62L surface markers within CD4+T cells to determine the frequency of naïve population in purified CD4+T cells. (B) Representative western blot showing protein levels of MT-CO1 (Complex IV) and SDHA (Complex II) in Th1 and Th2 cells treated with Veh and CHL. (C–E) Plots showing the activity of mitochondrial ETC Complex IV (C), ETC complex II (D) and citrate synthase (E) in Th1 and Th2 cells. (F) ATP levels estimated in the Veh and CHL-treated Th1 and Th2 cells. (G) Relative mitochondrial DNA copy number quantified using qRT-PCR in Veh and CHL-treated Th1 and Th2 cells. (H) Representative western blot showing protein levels of Drp1 and Mfn2 in Veh and CHL-treated CD4+T cells activated under neutral conditions. Graphs show mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 by paired t-test (C–G). The number of samples is denoted by the dots in the graphs. |
| imm13860-sup-0002-FigureS2.pdfPDF document, 1,012 KB | Figure S2. Mitochondrial translation inhibition reduces proliferation and effector functions of T cells. (A & B) Barplots showing the gene ontology terms enriched in CHL-treated Th1 (A) and Th2 (B) cells. The analysis was done using IPA software (Qiagen). (C & D) Representative western blots for p-S6 and S6 protein levels in the Veh and CHL-treated CD4+T cells in Th1 (C) and Th2 (D) conditions. (E) A bar plot showing the gene ontology terms enriched in the PC1 shown in Figure 2d. (F) Representative FACS plots showing the expression of IFN-γ in the Veh and CHL-treated CD4+T cells under neutral and Th1 polarizing conditions. (G & H). Plots showing cell counts of Th1 (G) and Th2 (H) after 48 h of rest (with IL-2, without anti-CD3/CD28 or antibiotic) of these cells that were activated for 72 h in the presence of the Veh or CHL. (I) Schematics of reactivation of Th1 and Th2 cells: Th1 and Th2 cells were reactivated with anti-CD3/CD28 for 24 h after 48 h of rest in IL-2 without CHL. Graphs show mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 by paired t-test (G & H). The number of samples is denoted by the dots in the graphs. |
| imm13860-sup-0003-FigureS3.pdfPDF document, 869.6 KB | Figure S3. CHL induces apoptosis in Th2 cells. (A) Quantification of T-bet and GATA-3 expressing cells in activated T cells in non-polarizing conditions expressed as the percentage of CD4+T-bet+cells and CD4+GATA-3+ cells. (B) Diagram showing the in vitro activation and differentiation of naive CD4+ T cells for 72 h followed by antibiotic treatment during culture with IL-2 for 72 h. (C) Cell count of Th1 and Th2 cells cultured with CHL for 3 days. The experimental schematic shown in Figure S3B was followed. (D & E) Quantification of proliferation based on cell trace violet (CTV) dye dilution staining after antibiotic treatment of Th1 (D) and Th2 cells (E). The experimental schematic shown in Figure S3B was followed. (F) Quantification of the frequency of live and apoptotic cells measured using Annexin and SYTOX staining in Th1 and Th2 cells treated with Veh and CHL. The experimental schematic shown in Figure 1a was followed. (G) Quantification of caspase 3/7 activity in Veh and CHL-treated Th1 and Th2 cells expressed as the percentage of Caspase 3/7+ cells. The experimental schematic shown in Figure 1a was followed. (H & I) Representative flow plots (H) and accompanying quantification (I) of Annexin V versus Propidium Iodide staining of Th1 and Th2 cells following treatment with 50 μM CHL. The numbers within the plots indicate the percentage of cells in each quarter (Q1–Q4). The experimental schematic shown in Figure S3B was followed. Graphs show mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 by paired t-test (A, C, D, E, F, G, I). The number of samples is denoted by the dots in the graphs. |
| imm13860-sup-0004-FigureS4.pdfPDF document, 531.4 KB | Figure S4. Bim and Puma are upregulated in CHL-treated Th2 cells. (A) Plot showing the mean fluorescence intensity (MFI) of CD95 in Th1 vs Th2 cells measured using FACS. (B) Quantification of FLIP mRNA levels in Th1 and Th2 cells using real-time qPCR. (C) Quantification of the frequency of apoptotic cells in Th1 and Th2 conditions measured using Annexin V staining. (D & E) Naïve CD4+T cells were differentiated into Th1 and Th2 for 3 days and then cultured in IL-2 for subsequent 3 days and subjected to flow cytometric analysis to determine the percentage of live (D) and apoptotic cells (E). (F) Volcano plot showing the apoptosis-related differentially expressed genes in Th1 (left panel) and Th2 (right panel) cells treated with CHL, compared with their Veh-treated counterparts. Red colour dots indicate genes upregulated in CHL-treated cells, and the golden colour dots indicate downregulated genes in CHL-treated cells. Graphs show mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 by paired t-test (A–E). The number of samples is denoted by the dots in the graphs. |
| imm13860-sup-0005-FigureS5.pdfPDF document, 879.1 KB | Figure S5. Th2 cells shows higher dependency on oxidative phosphorylation. (A) Heatmap showing expression of genes involved in glycolysis in Th1 and Th2 cells. Values for the heatmap are row normalized. (B & C) Plot showing basal and compensatory glycolysis in Th1 (B) and Th2 (C) cells treated with Veh and CHL as measured using glycolytic rate assay test. (D) Representative FACS plot of Annexin V versus Propidium Iodide staining of Th1 and Th2 cells following treatment with different conc. (0, 0.5, 0.8, 1 and 2 mM) of 2-DG for 72 h. Graphs show mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 by paired t-test (B & C). The number of samples is denoted by the dots in the graphs. |
| imm13860-sup-0006-FigureS6.pdfPDF document, 1.3 MB | Figure S6. Metabolic differences and differential response to CHL are conserved in human Th1 and Th2 cells. (A) Flow cytometric cell sorting strategy for isolation of naïve CD4+T cells from healthy donors. (B) Diagram showing the strategy for in vitro activation and differentiation of primary CD4+T cells followed by antibiotic treatment during reactivation. (C) Representative flow cytometric analysis of IFN-γ expression in Th1 and Th2 cells at day 15 of culture after PMA/ionomycin restimulation. (D) Relative mRNA expression of IL-4 in Th1 and Th2 cells after PMA/ionomycin restimulation. (E) Quantification of 2-NBDG uptake in Th1 and Th2 cells. A representative flow histogram for the same is given in Figure 6b. (F) Relative mRNA expression of the glycolytic enzyme LDHA in Th1 and Th2 cells. (G & H) Analysis of oxygen consumption rate (OCR) in Th1 and Th2 cells (G) and CHL-treated Th1 and Th2 (H) cells using a Seahorse extracellular flux analyser. (I) Cell count in Th1 and Th2 cells cultured with different conc. of CHL (25, 50 and 100 μM) for 5 days using automated cell counter. (J) Representative flow plots showing the cell trace violet (CTV) dye dilution in Th1 and Th2 cells treated with 100 μM CHL. (K) Quantification of MFI of 2-NBDG staining in Th1(left) and Th2 (right) cell treated with 100 μM CHL. (L) Glycolytic proton efflux rate (glycoPER) of Th1 (left) and Th2 (right) cells treated with 100 μM CHL as determined using a Seahorse extracellular flux analyser. Graphs show mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 by paired t-test (D–I, K & L). The number of samples is denoted by the dots in the graphs. |
| imm13860-sup-0007-TableS1.docxWord 2007 document , 28.3 KB | Table S1. Reagents used. |
| imm13860-sup-0008-TableS2.docxWord 2007 document , 10.4 KB | Table S2. Primers used in the study. |
| imm13860-sup-0009-DataS1.xlsxExcel 2007 spreadsheet , 5.1 MB | Data S1. Supporting information. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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