DataSheet_1_High BTLA Expression Likely Contributes to Contraction of the Regulatory T Cell Subset in Lupus Disease.pdf

B and T lymphocyte attenuator (BTLA) is a co-inhibitory receptor that is expressed by lymphoid cells and regulates the immune response. Consistent with an inhibitory role for BTLA, the disease is exacerbated in BTLA-deficient lupus mice. We recently demonstrated that the BTLA pathway is altered in CD4+ T cells from lupus patients. In the present work, we aimed at delineating the expression pattern of BTLA on CD4+ T cell subsets suspected to play a key role in lupus pathogenesis, such as circulating follicular helper T cells (cTFH) and regulatory T cells (Tregs). We did not detect significant ex vivo variations of BTLA expression on total CD4+ T cells (naive and memory), cTFH or TFH subsets between lupus patients and healthy controls. However, we interestingly observed that BTLA expression is significantly increased on activated Tregs, but not resting Tregs, from lupus patients, especially those displaying an active disease. Moreover, it correlates with the diminution of the Tregs frequency observed in these patients. We also showed that both BTLA mRNA and protein expression remain low after TCR stimulation of activated Tregs sorted from healthy donors and evidenced a similar dynamic of BTLA and HVEM expression profile by human Tregs and effector CD4+ T cells upon T cell activation than the one previously described in mice. Finally, we observed that the HVEM/BTLA ratio is significantly lower in Tregs from lupus patients compared to healthy controls, whereas ex vivo effector CD4+ T cells express higher BTLA levels. Our data suggest that an altered expression of BTLA and HVEM could be involved in an impaired regulation of autoreactive T cells in lupus. These results provide a better understanding of the BTLA involvement in lupus pathogenesis and confirm that BTLA should be considered as an interesting target for the development of new therapeutic strategies.

B和T淋巴细胞衰减因子（BTLA）是一种由淋巴样细胞表达的共抑制性受体，它调节免疫反应。与BTLA的抑制性作用一致，BTLA缺陷型狼疮小鼠的病情加剧。我们最近证明，狼疮患者的CD4+ T细胞中BTLA通路发生了改变。在本研究中，我们旨在描绘BTLA在CD4+ T细胞亚群中的表达模式，这些亚群在狼疮发病机制中可能发挥关键作用，如循环滤泡辅助性T细胞（cTFH）和调节性T细胞（Tregs）。我们未在狼疮患者与健康对照组的总CD4+ T细胞（原始和记忆细胞）、cTFH或TFH亚群之间检测到BTLA表达的显著差异。然而，我们有趣地观察到，BTLA在狼疮患者的活化Tregs上的表达显著增加，而在静息Tregs上则没有这种增加，特别是在那些表现出活动性疾病的患者中。此外，这一现象与这些患者中观察到的Tregs频率降低有关。我们还展示了来自健康捐赠者的活化Tregs在TCR刺激后，BTLA mRNA和蛋白质表达保持较低水平，并证实了BTLA和HVEM表达谱在人类Tregs和效应性CD4+ T细胞活化后的人体动态与之前在小鼠中描述的相似。最后，我们发现与健康对照组相比，狼疮患者的Tregs中HVEM/BTLA比率显著降低，而体外效应性CD4+ T细胞表达更高的BTLA水平。我们的数据表明，BTLA和HVEM表达的改变可能涉及狼疮中自反应性T细胞的调节受损。这些结果加深了对BTLA在狼疮发病机制中作用的理解，并证实BTLA应被视为开发新治疗策略的有趣靶点。