T Cell Memory

T细胞记忆

• 批准号: 7733340
• 负责人: Jonathan Ashwell
• 金额: $ 28.8万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7733340
• 关键词: Antigen Receptors; Antigens; Apoptosis; CD44 gene; CD8B1 gene; Cell Cycle; Cell Death; Cell Survival; Cell surface; Cells; Characteristics; Chronic; Clonal Expansion; DNA; Defect; Dendritic Cells; Disease; Drug or chemical Tissue Distribution; Exposure to; G1 Phase; Generations; Goals; Haploidy; Homing; Human; Immune; Immune response; Immune system; Immunologic Memory; Individual; Influenza; Interferon-alpha; Interphase Cell; Kinetics; Life; Lymphocyte Homing Receptors; Lymphocytic choriomeningitis virus; Lymphoid Tissue; Memory; Methods; Mus; Peptide/MHC Complex; Physiological; Play; Population; Property; Readiness; Role; SELL gene; T memory cell; T-Cell Receptor; T-Lymphocyte; Tumor Necrosis Factor Receptor; Use of New Techniques; Vaccination; Vesicular stomatitis Indiana virus; Viral; Work; base; cytokine; density; in vivo; lymph nodes; member; neoplastic; pathogen; prevent; receptor; response; Antigen Receptors; Antigens; Apoptosis; CD44 gene; CD8B1 gene; Cell Cycle; Cell Death; Cell Survival; Cell surface; Cells; Characteristics; Chronic; Clonal Expansion; DNA; Defect; Dendritic Cells; Disease; Drug or chemical Tissue Distribution; Exposure to; G1 Phase; Generations; Goals; Haploidy; Homing; Human; Immune; Immune response; Immune system; Immunologic Memory; Individual; Influenza; Interferon-alpha; Interphase Cell; Kinetics; Life; Lymphocyte Homing Receptors; Lymphocytic choriomeningitis virus; Lymphoid Tissue; Memory; Methods; Mus; Peptide/MHC Complex; Physiological; Play; Population; Property; Readiness; Role; SELL gene; T memory cell; T-Cell Receptor; T-Lymphocyte; Tumor Necrosis Factor Receptor; Use of New Techniques; Vaccination; Vesicular stomatitis Indiana virus; Viral; Work; base; cytokine; density; in vivo; lymph nodes; member; neoplastic; pathogen; prevent; receptor; response

Upon primary exposure to antigen, nave T cells bearing complementary antigen receptors (TCRs) undergo rapid activation and clonal expansion, leading to the generation of effector T cells. The vast majority (90-95%) of antigen-specific effector T cells that participate in the primary immune response undergo apoptosis (cell death) after antigen clearance. A small subset, however, survives and gives rise to long-lived memory T cells. Upon antigen re-encounter, memory T cells respond swiftly and robustly to eliminate the pathogen. Based on their tissue distribution, cell surface markers, and effector functions, memory T cells have been divided into two major subsets. Memory T cells expressing receptors such as CD62L and CCR7, which allow efficient homing to lymph nodes (LN), are termed central memory (TCM) cells; memory T cells lacking LN-homing receptors and preferentially residing in non-lymphoid tissues are termed effector memory (TEM) cells. Notably, both memory subsets display high levels of the marker CD44. Once established CD4 and CD8 memory T cell populations can be maintained for many years in vivo. Although early studies suggested that continued antigenic stimulation is required for maintaining T cell memory, neither cognate antigen nor MHC-encoded molecules appear to be required for the long-term survival of CD4 or CD8 memory T cells. Members of the tumor necrosis factor receptor (TNFR) family are involved in T cell costimulation and play a role in T cell survival. Mice deficient in OX40, CD27, or 4-1BB show greater defects in secondary compared to primary responses when infected with pathogens such as lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus, and influenza. Working primarily in mice, have developed a method of separating naive from memory T cells based upon their density. Using this new technique, we have made the following findings (especially with regard to CD8 T cell memory, which is important in anti-viral and anti-neoplastic responses): 1. Memory T cells exist in the G1 phase (high RNA, haploid DNA) of the cell cycle, whereas naive T cells exist in G0 (low RNA, haploid DNA). Stimulation of the former results in rapid release of high amounts of cytokines such as interferon alpha (IFNalpha). 2. Culture of purified memory T cells in the absence of other cells (resting) allows them to revert to G0. When they do, they respond to stimulation to the same degree and with the same kinetics as naive T cells. 3. Culture of memory T cells with purified dendritic cells (DC) prevents their reversion to G0 and maintains their characteristic potent effector responses. 4. Blockade of two TNFR molecules, CD70 and 4-1BB reverses the "protection" provided by DC. Furthermore, direct stimulation of the CD70 receptor on T cells, CD27, also maintains T cells in the memory state in the absence of any other cells. 5. All of these results were verified with memory T cells generated against lymphocytic choriomeningitis virus (LCMV) and identified by MHC-peptide "tetramers", which can identify individual antigen-specific cells. In preliminary studies, we found that human memory T cells also exist in G1, and in some cases we have been successful in "reverting" them to G0. Manipulating the memory T cell state of readiness might be of benefit in disorders involving chronic ongoing immune responses.

一级暴露于抗原时，带有互补抗原受体（TCR）的中含Have T细胞会经历快速激活和克隆膨胀，从而导致效应T细胞的产生。抗原清除后，参与原发性免疫反应的绝大多数（90-95％）抗原特异性效应T细胞会经历凋亡（细胞死亡）。然而，一个小子集生存并产生长寿命的记忆T细胞。抗原重新探测后，记忆T细胞迅速而稳健地反应以消除病原体。根据其组织分布，细胞表面标记和效应子功能，记忆T细胞已分为两个主要子集。表达受体（例如CD62L和CCR7）的记忆T细胞，这些受体允许有效地归因于淋巴结（LN），称为中央记忆（TCM）细胞； 缺乏LN的受体和优先驻留在非淋巴组织中的记忆T细胞称为效应子记忆（TEM）细胞。值得注意的是，两个内存子集都显示出高级别的标记CD44。一旦建立的CD4和CD8记忆T细胞种群可以在体内维持多年。尽管早期的研究表明，维持T细胞记忆需要持续的抗原刺激，但对于CD4或CD8记忆T细胞的长期存活似乎不需要同源抗原和MHC编码的分子。肿瘤坏死因子受体（TNFR）家族的成员参与T细胞共刺激，并在T细胞存活中起作用。与原发性反应相比，缺乏OX40，CD27或4-1BB的小鼠在感染了病原体（例如淋巴细胞脉络膜脑膜炎病毒（LCMV）），小囊炎病毒和流感时的主要反应显示出更大的缺陷。主要在小鼠中工作，已经开发了一种根据记忆T细胞的密度将天真分离的方法。使用这种新技术，我们做出了以下发现（尤其是关于CD8 T细胞存储器，这在抗病毒和抗塑性反应中很重要）：1。记忆T细胞存在于细胞周期的G1相（高RNA，单倍体DNA）中，而G0中存在天真的T细胞（低RNA，低RNA，Haploid DNA）。对前者的刺激导致大量细胞因子（例如干扰素α（Ifnalpha））迅速释放。 2。在没有其他细胞（静止）的情况下纯化的记忆T细胞的培养使它们可以恢复为G0。当他们这样做时，他们对刺激的程度和动力学与幼稚T细胞相同。 3。具有纯化的树突状细胞（DC）的记忆T细胞的培养可以防止其重新转换为G0并保持其特征性的有效效应子响应。 4.两个TNFR分子CD70和4-1BB的阻塞逆转了DC提供的“保护”。此外，在没有任何其他细胞的情况下，在T细胞上直接刺激CD27上的CD27受体也将T细胞保持在记忆状态。 5。所有这些结果均用针对淋巴细胞绒毛膜炎病毒（LCMV）产生的记忆T细胞验证，并通过MHC肽“四聚体”鉴定，该细胞可以鉴定可以鉴定单个抗原特异性细胞。在初步研究中，我们发现人类记忆T细胞也存在于G1中，在某些情况下，我们已经成功地将它们“恢复”为G0。操纵记忆的记忆状态的准备状态可能在涉及长期持续免疫反应的疾病中有益。