Kaposi's Sarcoma-Associated Herpesvirus Inhibits Expression and Function of Endothelial Cell Major Histocompatibility Complex Class II via Suppressor of Cytokine Signaling 3
Kaposi's Sarcoma-Associated Herpesvirus Inhibits Expression and Function of Endothelial Cell Major Histocompatibility Complex Class II via Suppressor of Cytokine Signaling 3
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DOI：
10.1128/jvi.06908-11
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发表时间：
2012-07-01
影响因子：
5.4
通讯作者：
Blackbourn, D. J.
中科院分区：
文献类型：
--
作者：
Butler, L. M.;Jeffery, H. C.;Blackbourn, D. J.
内皮细胞（EC）可通过组成型表达的主要组织相容性复合体I（MHC-I）将抗原呈递给CD 8（+）T淋巴细胞，或通过γ干扰素（IFN-γ）诱导的MHC-II将抗原呈递给CD 4（+）T淋巴细胞。卡波西肉瘤相关疱疹病毒（KSHV）是卡波西肉瘤（KS）的病原体，卡波西肉瘤是一种EC肿瘤，其特征是血管生成失调和大量炎症浸润。据了解，KSHV已发展出抑制EC上MHC-I表达和原发性渗出性淋巴瘤细胞上MHC-II表达的策略，但其对EC MHC-II表达的影响尚不清楚。在这里，我们报告说，KSHV感染的人原发性EC抑制IFN-γ诱导的MHC-II分子HLA-DR在转录水平上的表达。这种效应在功能上是显著的，因为HLA-DR限制性CD 4（+）T细胞克隆对KSHV感染EC呈递的同源抗原的识别减弱。HLA-DR表达的抑制也通过在IFN-γ处理之前将EC暴露于KSHV接种的EC的上清液来实现，揭示了可溶性介质的作用。IFN-γ诱导的STAT-1磷酸化和CHTA转录在KSHV接种EC中通过涉及SOCS 3（细胞因子信号转导抑制因子3）的机制受到抑制。因此，KSHV感染导致SOCS 3的转录上调，并且用针对SOCS 3的RNA干扰治疗减轻了病毒诱导的对IFN-γ诱导的STAT-1磷酸化的抑制。由于细胞表面MHC-II分子将肽抗原呈递给CD 4（+）T淋巴细胞，这些T淋巴细胞可以作为直接的细胞溶解效应物或启动和调节适应性免疫应答，因此抑制这种抗原呈递途径将为病毒提供存活优势。
Endothelial cells (EC) can present antigen to either CD8(+) T lymphocytes through constitutively expressed major histocompatibility complex class I (MHC-I) or CD4(+) T lymphocytes through gamma interferon (IFN-gamma)-induced MHC-II. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), an EC neoplasm characterized by dysregulated angiogenesis and a substantial inflammatory infiltrate. KSHV is understood to have evolved strategies to inhibit MHC-I expression on EC and MHC-II expression on primary effusion lymphoma cells, but its effects on EC MHC-II expression are unknown. Here, we report that the KSHV infection of human primary EC inhibits IFN-gamma-induced expression of the MHC-II molecule HLA-DR at the transcriptional level. The effect is functionally significant, since recognition by an HLA-DR-restricted CD4(+) T-cell clone in response to cognate antigen presented by KSHV-infected EC was attenuated. Inhibition of HLA-DR expression was also achieved by exposing EC to supernatant from KSHV-inoculated EC before IFN-gamma treatment, revealing a role for soluble mediators. IFN-gamma-induced phosphorylation of STAT-1 and transcription of CHTA were suppressed in KSHV-inoculated EC via a mechanism involving SOCS3 (suppressor of cytokine signaling 3). Thus, KSHV infection resulted in transcriptional upregulation of SOCS3, and treatment with RNA interference against SOCS3 relieved virus-induced inhibition of IFN-gamma-induced STAT-I phosphorylation. Since cell surface MHC-II molecules present peptide antigens to CD4(+) T lymphocytes that can function either as direct cytolytic effectors or to initiate and regulate adaptive immune responses, inhibition of this antigen-presenting pathway would provide a survival advantage to the virus.