Table 3:
Mechanistic studies of DN T cells in systemic lupus erythematosus and lupus nephritis
| Experimental design |
Mechanistic findings | Reference | |
|---|---|---|---|
| Model | Species/strain | ||
|
| |||
| SLE | Human blood DN T cells from clinically active SLE patients | -In vitro culture of DN T cells from SLE patients → ↑ DN T cell frequency and ↑ IgG-class anti-DNA autoantibodies compared to normal and inactive SLE via IL-2 mechanism -Active SLE → majority (72%) CDw29+ DN T cells subset |
Shivakumar S et al. (1989)40 |
|
| |||
| SLE | Human DN T cells from SLE patients and healthy controls (HC) blood samples | -SLE patients → ↑ DN T cells compared to HC -In vitro coculture of DN T cells from SLE patient + CD11+ APCs → IL-4 and IFN-γ -In vitro coculture of DN T cells from HCs → IFN-γ, no production of IL-4 -In vitro coculture of DN T cells from SLE patient + CD11+ APCs → IL-4 production and ↑ IgG1 compared to HC -IgG production from CD1c+ B cells depends on T cell activation through CD1c → Ab production via IL-4 and CD40L interaction |
Sieling PA et al. (2000)41 |
|
| |||
| SLE | Human DN T cells from SLE patients, RA patients, and HC blood samples | -SLE → ↑ TCRαβ+ DN T cell percentage of total DN T cell population compared to RA and HC -SLE → ↑ HLA-DR+ DN T cells, ↑ CD69+ DN T cells, ↑ CTLA4+ DN T cells, ↑ CD28+ DN T cell number compared to RA and HC |
Anand A et al. (2002)42 |
|
| |||
| SLE In vitro experiments |
Human DN T cells from female SLE patients and HC. Prednisone was paused at least 24h before blood draw | -In vitro culture of DN T cells from SLE patients→ ↑ IL-17+ DN T cells at basal culture conditions and after 5d of culture compared to IL-17+ CD4+ T cells -In vitro anti-CD3 stimulation of DN T cells from SLE patients → 5 days → ↑ DN T frequency -In vitro cultured DN T produce ↓ IL-2, ↑TNF-α, and ↑IFN-γ compared to CD4+ T cells (SLE patients and HC) -In vitro cultured DN T cells from SLE → ↑ IL-17+ DN T compared to DN T cells from HCs |
Crispin JC et al. (2008)43 |
| Kidney biopsies of SLE patients | -SLE patients’ kidney biopsies → DN T cells with positive immunofluorescent staining of IL-17 and IL-23 | ||
|
| |||
| SLE In vivo and in vitro experiments |
MRL/lpr mice | -In vitro IL-23 stimulation of DN T cells → ↑IL-17 expression compared to control cells -AT of stimulated MRL/lpr DN T → nephritis in Rag-1−/− mice (deposition of Ig and C3d in glomeruli) |
Zhang Z et al. (2009)44 |
|
| |||
| SLE | Mice, IL-23R deficient C57BL/6 | -IL-23-R KO B6/lpr mice protected from SLE, ↓ DN T cell number and percentage of IL-17+ DN T cells, ↓ IFN-γ, ↓ IgG and anti-dsDNA Abs compared to B6/lpr mice | Kyttaris VC et al. (2010)45 |
|
| |||
| SLE | Human DN cells from SLE patients and HC | -SLE → ↑ mTOR activity in DN T and ↓ D3+CD4+CD25+ FoxP3+T cells -SLE → ↑IL-4 of DN T cells, correlating with production of anti-DNA Ab -Rapamycin treatment of SLE patients → ↓ necrosis and ↓ IL-4 production of DN T (↓MFI) -No changes in DN IL4+ T cells or DN IL17+ T percentage |
Lai Z et al. (2013)46 |
|
| |||
| SLE | Mice, WT C57BL/6 and double KO IL-17−/−/Stat−/− Pristane lupus induction | -IL-17 KO mice protected from pristane induced SLE, ↓ DN T -IL-17 deficiency → protection from SLE independent of Stat1 activity and ↓ DN T and ↑ Tregs -IL-17 → anti-ssDNA, anti-nRNP and anti-chromatin autoantibody production |
Amarilyo G et al. (2014)47 |
|
| |||
| SLE | Mice, MRL/lpr− | -IL-2 (usage of IL-2-recombinant adeno-associated virus) → ↓ IL-17+ DN T cells by inducing cell death -IL-2/anti–IL-2 Ab complex and targeting of IL-2 to cytotoxic lymphocytes → ↓ DN T cells and INF-γ, no change of anti-dsDNA antibody production -IL-2 → ↑ DN T cell death via CD122 receptor and STAT5 phosphorylation by IL-2 on CD8+ T cells. |
Mizui M et al. (2014)48 |
|
| |||
| SLE | Female MRL-lpr mice | -A77 1726 (active metabolite of leflunomide) treatment → ↓ lupus activation (↓anti-dsDNA, ↓anti-ANA, ↓ inflammation in kidney histology samples) -A77 1726 treatment → Akt dependent ↑ CD3+CD4+CD25+FoxP3 + T cells → ↓ splenic IL17+ DN T |
Qiao G et al. (2015)31 |
|
| |||
| SLE | B6/lpr CXCR5−/− mice | -AT of DN T cells of B6/lpr CXCR5−/− → ↓ CD3+ in recipient Rag−/− mice compared to controls receiving B6/lpr DN T cells | Wiener A et al. (2016)49 |
| In vitro studies | -In vitro trans-well studies → ↓ chemotactic response of splenic DN T cells towards CXCL13 compared to control B6/lpr DN T | ||
|
| |||
| SLE | Human blood sample of SLE patients | -IL-23 treatment → ↑ SLE DN T numbers independent of Tfh markers and ↑ IL-17 production in vitro -IL-23 treatment → ↓ IFN-γ and IL-2 by SLE T cells in vitro via suppression of NFkBp65 (IL-2 enhancer) → ↑ Tfh cells → ↑ anti-dsDNA independent of DN T |
Dai H et al. (2017)50 |
| Mice, IL-23R−/−MRL-lpr | -IL-23R deficiency → ↓ CD45+ DN T infiltration, DN T cells dominant T cell subset, ↓ IL-17 and ↓IFN-γ in SLE kidney model -IL-23 treatment → ↑ IL-17+ T cells and ↑IL-17 production in vitro -IL-23+/+ MRL-lpr → ↑ CD4+ T cells becoming DN T compared to IL-23 KO MRL-lpr and control MRL-MPJ mice -IL-23+/+ MRL-lpr → ↑ DN T proliferation compared to IL-23 KO MRL-lpr in spleen and peripheral lymph nodes -IL-23−/− MRL-lpr → ↑ IL-2 compared to WT MRL-lpr in vitro |
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|
| |||
| SLE | IFN-α Tg Mice | -IFN-α Tg Mice express ↑ IFN-α and develop SLE manifestations (glomerulonephritis) -↑ IFN-α leads to ↑ CD69+ IFN-γ+ DN T in kidney |
Akiyama C et al. (2019)51 |