Mobilizing TAP-independent CD8 T cells through non-canonical cross-presentation

建议书摘要 主要组织相容性复合体I类(MHC-I)分子在细胞表面呈递多肽给CD8T细胞。 与抗原处理相关的转运蛋白(TAP)是TAP1和TAP2的异二聚体分子，它 位于大分子多肽负载复合体的中心，负责负载和折叠MHC-I分子 用多肽。TAP将胞浆蛋白酶体产生的多肽穿梭在内质膜上 用于腔内运输和装载MHC-I分子的网状结构(ER)。鉴于TAP在运输过程中的关键作用 多肽到MHC-I分子，许多临床上重要的人类病毒，如疱疹病毒科和痘病毒科 已经进化出了阻止TAP和逃避宿主CD8 T细胞识别的策略。被感染后的窃听封锁 负责初始CD8 T细胞启动的树突状细胞(DC)损害了传统的TAP-蛋白酶体 处理经典的MHC-I多肽递呈给CD8T细胞。事实上，当前的范式认为 阻断DC中的TAP使这些细胞失去功能，不能启动CD8 T细胞反应。引爆 病毒特异性CD8T细胞通过交叉呈现，落在未感染的TAP足够的旁观者DC上，这是一个过程 这使得MHC-I能够装载来自DC内化的病毒感染的垂死细胞的病毒肽。然而， 由TAP充足的DC激活的CD8T细胞识别主要的TAP依赖的多肽，其呈现方式是 在感染免疫逃避病毒的组织上严重减少。依赖TAP的CD8 T细胞也会 与通过病毒的TAP非依赖性替代处理而释放的TAP非依赖性多肽不匹配 抗原，并由MHC-I递呈在感染组织上。任何一种情况都会产生减少或不匹配的 CD8T细胞靶点。免疫系统是如何解决这个问题的？我们发现DC没有官能团 TAP依赖于细胞自主地从一个新的位置--ER-Golgi中间隔室递送MHC-I (ERIGIC)，内化抗原，以挽救MHC-I递呈，但仍交叉启动CD8 T细胞。我们 我们称这条路径为非规范的交叉陈述。我们的发现指出，非规范的交叉陈述是一种 识别TAP非依赖表位的CD8 T细胞的启动途径此前未知 是对抗免疫躲避病毒的最佳匹配。研究非规范的交叉陈述对于 了解可被动员起来抵御感染的CD8 T细胞的全谱，特别是当这种T细胞 在受感染的组织内提供有效的局部交叉保护。我们试图理解非规范的角色 在启动抗病毒感染的非TAP依赖的CD8 T细胞反应中的交叉呈现。使用新的模型， 我们将确定执行非规范交叉演示的DC，并定义与TAP无关的曲目 它们呈现给抗原特异的TAP非依赖性CD8T细胞的表位。我们将创建新的工具来跟踪TAP- 独立的CD8 T细胞反应，并确定非规范的交叉呈现是否可以推动交叉- 针对病毒变种和免疫逃避病毒的保护性免疫。理解非正则交叉 演讲将为针对慢性和持续性病毒感染的普遍疫苗设计和新疗法提供信息。

PROPOSAL SUMMARY Major histocompatibility complex class I (MHC-I) molecules present peptides at the cell surface to CD8 T cells. The transporter associated with antigen processing (TAP) is a heterodimeric molecule of TAP1 and TAP2 that lies at the center of a macromolecular peptide loading complex tasked with loading and folding MHC-I molecules with peptides. TAP shuttles cytosolic proteasome-generated peptides across the membrane of the endoplasmic reticulum (ER) for luminal delivery and loading of MHC-I molecules. Given the crucial role of TAP in translocating peptides to MHC-I molecules, many clinically important human viruses such as Herpesviridae and Poxviridae have evolved strategies to block TAP and evade host CD8 T cell recognition. TAP blockade upon infection of dendritic cells (DC), which are responsible for naïve CD8 T cell priming, impairs conventional TAP-proteasome processing for the classic MHC-I presentation of peptides to CD8 T cells. In fact, the current paradigm holds that TAP blockade in DC renders these cells non-functional and incapable of priming a CD8 T cell response. Priming virus-specific CD8 T cells falls on uninfected TAP-sufficient bystander DC through cross-presentation, a process that enables MHC-I loading with viral peptides derived from DC internalized virus-infected dying cells. However, CD8 T cells primed by TAP-sufficient DC recognize dominant TAP-dependent peptides, whose presentation is severely reduced on tissues infected with immune evasive viruses. TAP-dependent CD8 T cells would also be mismatched to the TAP-independent peptides liberated by alternative TAP-independent processing of viral antigens and presented by MHC-I on those infected tissues. Either scenario creates a diminished or mismatched CD8 T cell target. How does the immune system get around this problem? We found that DC without functional TAP rely on cell-autonomous delivery of MHC-I from a new location, the ER-Golgi intermediate compartment (ERGIC), to internalized antigens to rescue MHC-I presentation and nevertheless cross-prime CD8 T cells. We call this pathway non-canonical cross-presentation. Our findings point to non-canonical cross-presentation as a previously unrecognized pathway for priming CD8 T cells that recognize TAP-independent epitopes and would be best-matched against immune evasive viruses. Studying non-canonical cross-presentation is important to understand the full spectrum of CD8 T cells that can be mobilized against infection, especially if such T cells provide potent local cross-protection within infected tissues. We seek to understand the role of non-canonical cross-presentation in priming a TAP-independent CD8 T cell response against viral infection. Using novel models, we will identify DC that conduct non-canonical cross-presentation, and define the repertoire of TAP-independent epitopes they present to antigen-specific TAP-independent CD8 T cells. We will create novel tools to track TAP- independent CD8 T cell responses and determine whether non-canonical cross-presentation can drive cross- protective immunity against viral variants and immune evasive viruses. Understanding non-canonical cross- presentation will inform universal vaccine design and new therapies for chronic and persistent viral infections.