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

ABSTRACT 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‐TCRβ (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‐TCRβ 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‐TCRβ mAb significantly prolonged the survival of MRL/ lpr mice. Accordingly, MRL/ lpr mice in the anti‐TCRβ mAb group exhibited decreased proteinuria scores and minimal renal pathological damage compared to the PBS control group. Flow cytometric analysis revealed that anti‐TCRβ mAb treatment resulted in a reduction in the frequencies of CD4 + T cells and CD138 + B220 lo/− plasma cells, plus an increase in Foxp3 + regulatory T cell frequency. Furthermore, CD4 + T cells from anti‐TCRβ mAb treated mice exhibited elevated expression levels of PD‐1 and TIM‐3, with reduced IFN‐γ production, indicative of an exhaustion‐like phenotype. Therefore, transient administration of anti‐TCRβ 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.