Decreased Levels of STAT1 and Interferon‐γ–Induced STAT1 Phosphorylation in Rheumatoid Arthritis CD4 and CD8 T Cells
Objective We investigated whether a previously reported association of IFNGR expression with rheumatoid arthritis (RA) and its radiographic severity reflects differences in proximal interferon‐γ (IFN‐γ) signaling in T cells from patients with RA compared with healthy controls (HC). Methods Using pho...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-04-01
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| Series: | ACR Open Rheumatology |
| Online Access: | https://doi.org/10.1002/acr2.11244 |
| _version_ | 1818330101568241664 |
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| author | Vishal Sharma Brandon J. Pope Nathan V. Santiago Molly T. Boland Dongmei Sun Richard J. Reynolds Alexander J. Szalai S. Louis Bridges Jr Chander Raman |
| author_facet | Vishal Sharma Brandon J. Pope Nathan V. Santiago Molly T. Boland Dongmei Sun Richard J. Reynolds Alexander J. Szalai S. Louis Bridges Jr Chander Raman |
| author_sort | Vishal Sharma |
| collection | DOAJ |
| description | Objective We investigated whether a previously reported association of IFNGR expression with rheumatoid arthritis (RA) and its radiographic severity reflects differences in proximal interferon‐γ (IFN‐γ) signaling in T cells from patients with RA compared with healthy controls (HC). Methods Using phosphoflow cytometry, we compared IFN‐γ–stimulated signal transducer and activator of transcription 1 (STAT1) activation in CD4+ and CD8+ T‐cell populations from patients with RA and HC. Results Compared with controls, patients with RA had a higher proportion of CD4+ T cells, associated with expansion of the CD4+ effector memory subset. Several CD4+ T‐cell types exhibited reduced IFN‐γ–induced phosphoSTAT1Y701 (pSTAT1Y701) in patients with RA compared with HC. Engaging the T‐cell receptor (TCR) complex on CD4+ T cells during IFN‐γ stimulation abrogated the reduction in STAT1 activation in patients with RA but had no effect in HC. The phosphorylation of STAT1S727 was similar in CD4+ T cells from patients with RA and HC. In contrast to CD4+ T cells, IFN‐γ–induced pSTAT1Y701 levels in CD8+ T cells were equivalent or higher in patients with RA compared with HC. Total STAT1 levels (phosphorylated + unphosphorylated) were lower in CD4+ and CD8+ T cells from patients with RA compared with HC. Conclusion We report diminished IFN‐γ–induced pSTAT1Y701 levels in CD4+ T cells in patients with RA, which were restored by TCR engagement. There were lower levels of total STAT1 in patients with RA compared with HC, but this likely does not explain diminished IFN‐γ–induced pSTAT1Y701 levels in CD4+ T cells because activation in CD8+ T cells was higher or equivalent to that seen in HC. The enhanced IFNGR expression in patients with RA reported previously may reflect a compensatory mechanism to overcome deficiency in IFN‐γ responsiveness. |
| first_indexed | 2024-12-13T12:58:36Z |
| format | Article |
| id | doaj.art-d888a192d9584d7eb732e45106c2557b |
| institution | Directory Open Access Journal |
| issn | 2578-5745 |
| language | English |
| last_indexed | 2024-12-13T12:58:36Z |
| publishDate | 2021-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | ACR Open Rheumatology |
| spelling | doaj.art-d888a192d9584d7eb732e45106c2557b2022-12-21T23:45:06ZengWileyACR Open Rheumatology2578-57452021-04-013427728310.1002/acr2.11244Decreased Levels of STAT1 and Interferon‐γ–Induced STAT1 Phosphorylation in Rheumatoid Arthritis CD4 and CD8 T CellsVishal Sharma0Brandon J. Pope1Nathan V. Santiago2Molly T. Boland3Dongmei Sun4Richard J. Reynolds5Alexander J. Szalai6S. Louis Bridges Jr7Chander Raman8The University of Alabama at BirminghamThe University of Alabama at BirminghamThe University of Alabama at BirminghamThe University of Alabama at BirminghamThe University of Alabama at BirminghamThe University of Alabama at BirminghamThe University of Alabama at BirminghamThe University of Alabama at BirminghamThe University of Alabama at BirminghamObjective We investigated whether a previously reported association of IFNGR expression with rheumatoid arthritis (RA) and its radiographic severity reflects differences in proximal interferon‐γ (IFN‐γ) signaling in T cells from patients with RA compared with healthy controls (HC). Methods Using phosphoflow cytometry, we compared IFN‐γ–stimulated signal transducer and activator of transcription 1 (STAT1) activation in CD4+ and CD8+ T‐cell populations from patients with RA and HC. Results Compared with controls, patients with RA had a higher proportion of CD4+ T cells, associated with expansion of the CD4+ effector memory subset. Several CD4+ T‐cell types exhibited reduced IFN‐γ–induced phosphoSTAT1Y701 (pSTAT1Y701) in patients with RA compared with HC. Engaging the T‐cell receptor (TCR) complex on CD4+ T cells during IFN‐γ stimulation abrogated the reduction in STAT1 activation in patients with RA but had no effect in HC. The phosphorylation of STAT1S727 was similar in CD4+ T cells from patients with RA and HC. In contrast to CD4+ T cells, IFN‐γ–induced pSTAT1Y701 levels in CD8+ T cells were equivalent or higher in patients with RA compared with HC. Total STAT1 levels (phosphorylated + unphosphorylated) were lower in CD4+ and CD8+ T cells from patients with RA compared with HC. Conclusion We report diminished IFN‐γ–induced pSTAT1Y701 levels in CD4+ T cells in patients with RA, which were restored by TCR engagement. There were lower levels of total STAT1 in patients with RA compared with HC, but this likely does not explain diminished IFN‐γ–induced pSTAT1Y701 levels in CD4+ T cells because activation in CD8+ T cells was higher or equivalent to that seen in HC. The enhanced IFNGR expression in patients with RA reported previously may reflect a compensatory mechanism to overcome deficiency in IFN‐γ responsiveness.https://doi.org/10.1002/acr2.11244 |
| spellingShingle | Vishal Sharma Brandon J. Pope Nathan V. Santiago Molly T. Boland Dongmei Sun Richard J. Reynolds Alexander J. Szalai S. Louis Bridges Jr Chander Raman Decreased Levels of STAT1 and Interferon‐γ–Induced STAT1 Phosphorylation in Rheumatoid Arthritis CD4 and CD8 T Cells ACR Open Rheumatology |
| title | Decreased Levels of STAT1 and Interferon‐γ–Induced STAT1 Phosphorylation in Rheumatoid Arthritis CD4 and CD8 T Cells |
| title_full | Decreased Levels of STAT1 and Interferon‐γ–Induced STAT1 Phosphorylation in Rheumatoid Arthritis CD4 and CD8 T Cells |
| title_fullStr | Decreased Levels of STAT1 and Interferon‐γ–Induced STAT1 Phosphorylation in Rheumatoid Arthritis CD4 and CD8 T Cells |
| title_full_unstemmed | Decreased Levels of STAT1 and Interferon‐γ–Induced STAT1 Phosphorylation in Rheumatoid Arthritis CD4 and CD8 T Cells |
| title_short | Decreased Levels of STAT1 and Interferon‐γ–Induced STAT1 Phosphorylation in Rheumatoid Arthritis CD4 and CD8 T Cells |
| title_sort | decreased levels of stat1 and interferon γ induced stat1 phosphorylation in rheumatoid arthritis cd4 and cd8 t cells |
| url | https://doi.org/10.1002/acr2.11244 |
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