Transient Anti-TCRβ mAb Treatment Induces CD4+ T Cell Exhaustion and Prolongs Survival in a Mouse Model of Systemic Lupus Erythematosus

被引:0
|
作者
Gonzalez, Nancy Mize [1 ,2 ]
Zou, Dawei [1 ]
Zeng, Zihua [3 ]
Feng, Frances Xiuyan [4 ]
Zhang, Xiaolong [1 ]
Sannes, Caitlin [1 ]
Gu, Andy [1 ]
Zu, Youli [3 ]
Chen, Wenhao [1 ,2 ,5 ]
机构
[1] Houston Methodist Hosp, Houston Methodist Res Inst, Immunobiol & Transplant Sci Ctr, Dept Surg, Houston, TX 77030 USA
[2] Texas A&M Univ, Coll Med, College Stn, TX 77840 USA
[3] Houston Methodist Hosp, Dept Pathol & Genom Med, Houston, TX USA
[4] Univ Colorado Anschutz Med Campus, Dept Pathol, Aurora, CO USA
[5] Cornell Univ, Dept Surg, Weill Cornell Med, New York, NY 14850 USA
关键词
CD4; cell; exhaustion; lupus/SLE; AUTOIMMUNITY; TH17;
D O I
10.1111/imm.13881
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). Chronic T cell receptor (TCR) signalling induces T cell exhaustion, characterised by reduced capacity to induce tissue damage. Here, we investigated the therapeutic potential of the anti-TCR beta (H57-597) monoclonal antibody (mAb) in a mouse model of SLE. Four-month-old MRL/lpr mice exhibiting SLE phenotypes received 5 weekly doses of anti-TCR beta mAb or phosphate-buffered saline (PBS) vehicle control. Subsequently, mouse survival was monitored daily. On day 1 post the final dose of treatment, SLE pathogenesis was determined using histological staining and spot urine test. T and B cell states in the brain, kidney, and secondary lymphoid organs were determined by flow cytometry. Transient treatment of anti-TCR beta mAb significantly prolonged the survival of MRL/lpr mice. Accordingly, MRL/lpr mice in the anti-TCR beta mAb group exhibited decreased proteinuria scores and minimal renal pathological damage compared to the PBS control group. Flow cytometric analysis revealed that anti-TCR beta mAb treatment resulted in a reduction in the frequencies of CD4+ T cells and CD138+B220lo/- plasma cells, plus an increase in Foxp3+ regulatory T cell frequency. Furthermore, CD4+ T cells from anti-TCR beta mAb treated mice exhibited elevated expression levels of PD-1 and TIM-3, with reduced IFN-gamma production, indicative of an exhaustion-like phenotype. Therefore, transient administration of anti-TCR beta mAb treatment induces an exhaustion-like phenotype in CD4+ T cells, resulting in prolonged survival of MRL/lpr mice. Inducing autoreactive T-cell exhaustion holds promise as an attractive therapeutic approach for SLE.
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收藏
页码:239 / 246
页数:8
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