The tumor necrosis factor receptor superfamily member HVEM is one of the most frequently mutated surface proteins in germinal center (GC)-derived B cell lymphomas. We found that HVEM deficiency increased B cell competitiveness during pre-GC and GC responses. The immunoglobulin (Ig) superfamily protein BTLA regulated HVEM-expressing B cell responses independently of B-cell-intrinsic signaling via HVEM or BTLA. BTLA signaling into T cells through the phosphatase SHP1 reduced T cell receptor (TCR) signaling and preformed CD40 ligand mobilization to the immunological synapse, thus diminishing the help delivered to B cells. Moreover, T cell deficiency in BTLA cooperated with B cell Bcl-2 overexpression, leading to GC B cell outgrowth. These results establish that HVEM restrains the T helper signals delivered to B cells to influence GC selection outcomes, and they suggest that BTLA functions as a cell-extrinsic suppressor of GC B cell lymphomagenesis.

中文翻译：

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HVEM-BTLA轴将T细胞帮助约束到生发中心B细胞，并在淋巴瘤发生中作为细胞外源性抑制剂发挥功能。

肿瘤坏死因子受体超家族成员HVEM是生发中心（GC）衍生的B细胞淋巴瘤中最常见的突变表面蛋白之一。我们发现HVEM缺乏会增加GC前和GC反应期间的B细胞竞争能力。免疫球蛋白（Ig）超家族蛋白BTLA独立于通过HVEM或BTLA的B细胞内在信号传导调节表达HVEM的B细胞反应。通过磷酸酶SHP1进入T细胞的BTLA信号传导减少了T细胞受体（TCR）信号传导，并实现了CD40配体动员到免疫突触，从而减少了对B细胞的帮助。此外，BTLA中的T细胞缺乏症与B细胞Bcl-2过表达协同作用，导致GC B细胞过度生长。