BTLA Interaction with HVEM Expressed on CD8⁺ T Cells Promotes Survival and Memory Generation in Response to a Bacterial Infection

The B and T lymphocyte attenuator (BTLA) is an Ig super family member that binds to the herpes virus entry mediator (HVEM), a TNF receptor super family (TNFRSF) member. Engagement of BTLA by HVEM triggers inhibitory signals, although recent evidence indicates that BTLA also may act as an activating ligand for HVEM. In this study, we reveal a novel role for the BTLA-HVEM pathway in promoting the survival of activated CD8+ T cells in the response to an oral microbial infection. Our data show that both BTLA- and HVEM-deficient mice infected with Listeria monocytogenes had significantly reduced numbers of primary effector and memory CD8+ T cells, despite normal proliferation and expansion compared to controls. In addition, blockade of the BTLA-HVEM interaction early in the response led to significantly reduced numbers of antigen-specific CD8+ T cells. HVEM expression on the CD8+ T cells as well as BTLA expression on a cell type other than CD8+ T lymphocytes, was required. Collectively, our data demonstrate that the function of the BTLA-HVEM pathway is not limited to inhibitory signaling in T lymphocytes, and instead, that BTLA can provide crucial, HVEM-dependent signals that promote survival of antigen activated CD8+ T cell during bacterial infection.B和T淋巴细胞衰减因子（B and T lymphocyte attenuator, BTLA）属于免疫球蛋白超家族成员，可结合疱疹病毒进入介导因子（herpes virus entry mediator, HVEM）——后者为肿瘤坏死因子受体超家族（TNF receptor super family, TNFRSF）成员。HVEM与BTLA结合可触发抑制性信号，但新近研究证据表明，BTLA亦可作为HVEM的激活型配体发挥功能。本研究揭示了BTLA-HVEM通路在口腔微生物感染的免疫应答中促进活化CD8+ T细胞存活的新功能。我们的实验数据显示，相较于对照组，单核细胞增多性李斯特菌（Listeria monocytogenes）感染的BTLA缺陷小鼠与HVEM缺陷小鼠的初级效应性及记忆性CD8+ T细胞数量均显著减少，但其增殖与扩增水平与对照组无明显差异。此外，在免疫应答早期阻断BTLA-HVEM的相互作用，可导致抗原特异性CD8+ T细胞数量显著降低。该过程需要CD8+ T细胞表面表达HVEM，同时也需要非CD8+ T淋巴细胞类群上表达BTLA。综上，本研究数据证实，BTLA-HVEM通路的功能并不局限于T淋巴细胞内的抑制性信号传导；相反，BTLA可提供关键的、依赖HVEM的信号，在细菌感染过程中促进抗原活化CD8+ T细胞的存活。