The role of antigenic strength in the primary and memory responses of pathogen sp

抗原强度在病原体的初级反应和记忆反应中的作用

基本信息

批准号：
8574124
负责人：
K. Scott Weber
金额：
$ 44.91万
依托单位：
BRIGHAM YOUNG UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8574124
关键词：
ALCAM gene Acquired Immunodeficiency Syndrome Activated-Leukocyte Cell Adhesion Molecule Address Affect Affinity Amino Acids Antigen-Presenting Cells Antigens Apoptosis Apoptotic BCL2 gene Binding Breeding CD4 Positive T Lymphocytes CD6 antigen CD8-Positive T-Lymphocytes Cell Death Cell Survival Cells Characteristics Communicable Diseases Complex Development Disease Epitopes Failure Future Generations Immune response Immune system Immunity Immunotherapy In Vitro Infection Influenza Knockout Mice Life Ligands Listeria monocytogenes Major Histocompatibility Complex Malaria Malignant Neoplasms Memory Mus Peptides Phenotype Play Population Positioning Attribute Proteins Role Signal Transduction Sorting - Cell Movement Staining method Stains System T cell response T memory cell T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Therapeutic Transgenes Transgenic Mice Tuberculosis Vaccine Design Vaccines Work annexin A5 design improved in vivo memory CD4 T lymphocyte mutant novel pathogen public health relevance receptor receptor binding response therapeutic vaccine

项目摘要

DESCRIPTION (provided by applicant): The development of more effective vaccines requires an understanding of the requirements for strong short and long-term immune responses. Memory cell formation is a hallmark of the adaptive immune system and CD4+ T cells play a central role in the generation of productive recall responses and protective immunity. CD4+ T cells coordinate the adaptive and innate immune responses to infection, but their role as memory cells is not well understood. An unresolved question is what CD4+ TCR:pMHC affinity leads to optimal CD4+ memory cell formation. To address this, we have recently generated two CD4+ TCR transgenic mouse lines that are specific for the same naturally occurring epitope from Listeria monocytogenes. The TCRs from these mice lines (LLO118 and LLO56) differ by only 15 amino acids and while LLO118 and LLO56 T cells have a similar in vitro response to antigen, their in vivo responses to infection are strikingly different. LLO118 has a stronger primary response whereas LLO56 has a much stronger memory response. Understanding why these TCRs cause such different T cell responses provides a novel system to understand how to improve vaccines and immunotherapies. In Aim 1, we have generated four L. monocytogenes mutants with different capacities to stimulate LLO118 and LLO56 T cells to test the role of TCR:pMHC binding affinity in CD4+ primary and memory responses. Additionally, we unexpectedly found that LLO56, the T cell with the best memory response, has higher levels of pro-apoptotic staining (Annexin V) after antigen stimulation. In Aim 2 we want to confirm this using additional apoptotic markers and determine how cell death is related to memory cell formation. Finally, we have found expression differences in two T cell co-receptors (CD5 and CD6) that negatively regulate T cell activation. These are both up-regulated in LLO56, which has the weaker primary response but stronger memory response, and in Aim 3 we will be using CD5 knockout mice and CD6L (CD166) knockout mice to determine their role in controlling the primary and memory responses of LLO118 and LLO56. Our studies have the potential to identify the characteristics of CD4+ T cells responsible for differential immune responses and this could be highly relevant for improving therapeutic and protective vaccine design and immunotherapies.

描述（由申请人提供）：开发更有效的疫苗需要了解强烈的短期和长期免疫反应的要求。记忆细胞的形成是适应性免疫系统的标志，CD4+ T 细胞在生产性回忆反应和保护性免疫的产生中发挥着核心作用。 CD4+ T 细胞协调对感染的适应性和先天免疫反应，但它们作为记忆细胞的作用尚不清楚。一个未解决的问题是 CD4+ TCR:pMHC 亲和力如何导致最佳 CD4+ 记忆细胞形成。为了解决这个问题，我们最近生成了两个 CD4+ TCR 转基因小鼠品系，它们对单核细胞增生李斯特菌中相同的天然表位具有特异性。这些小鼠系（LLO118 和 LLO56）的 TCR 仅相差 15 个氨基酸，虽然 LLO118 和 LLO56 T 细胞对抗原具有相似的体外反应，但它们对感染的体内反应却截然不同。 LLO118 具有更强的初级反应，而 LLO56 具有更强的记忆反应。了解这些 TCR 为何会导致如此不同的 T 细胞反应，为了解如何改进疫苗和免疫疗法提供了一个新的系统。在目标 1 中，我们生成了四种单核细胞增生李斯特菌突变体，它们具有不同的刺激 LLO118 和 LLO56 T 细胞的能力，以测试 TCR:pMHC 结合亲和力在 CD4+ 初级和记忆反应中的作用。此外，我们意外地发现，具有最佳记忆反应的T细胞LLO56在抗原刺激后具有更高水平的促凋亡染色（Annexin V）。在目标 2 中，我们希望使用额外的细胞凋亡标记物来证实这一点，并确定细胞死亡与记忆细胞形成之间的关系。最后，我们发现了两种 T 细胞辅助受体（CD5 和 CD6）的表达差异，它们对 T 细胞激活产生负调节。这些在 LLO56 中均上调，LLO56 的初级反应较弱，但记忆反应较强，在目标 3 中，我们将使用 CD5 敲除小鼠和 CD6L (CD166) 敲除小鼠来确定它们在控制初级反应和记忆反应中的作用。 LLO118 和 LLO56。我们的研究有可能确定负责差异免疫反应的 CD4+ T 细胞的特征，这可能与改善治疗性和保护性疫苗设计和免疫疗法高度相关。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Naïve helper T cells with high CD5 expression have increased calcium signaling.

具有高 CD5 表达的幼稚辅助 T 细胞增加了钙信号传导。

DOI：
发表时间：
2017
期刊：
影响因子：
3.7
作者：
Freitas, Claudia M Tellez;Hamblin, Garrett J;Raymond, Carlee M;Weber, K Scott
通讯作者：
Weber, K Scott

CD4 Inhibits Helper T Cell Activation at Lower Affinity Threshold for Full-Length T Cell Receptors Than Single Chain Signaling Constructs.

CD4 对全长 T 细胞受体的亲和力阈值低于单链信号传导构建体，从而抑制辅助 T 细胞的激活。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Johnson, Deborah K;Magoffin, Wyatt;Myers, Sheldon J;Finnell, Jordan G;Hancock, John C;Orton, Taylor S;Persaud, Stephen P;Christensen, Kenneth A;Weber, K Scott
通讯作者：
Weber, K Scott

The nuclear variant of bone morphogenetic protein 2 (nBMP2) is expressed in macrophages and alters calcium response.

骨形态发生蛋白 2 (nBMP2) 的核变体在巨噬细胞中表达并改变钙反应。

DOI：
发表时间：
2019
期刊：
影响因子：
4.6
作者：
Tellez Freitas, Claudia M;Burrell, Haley R;Valdoz, Jonard C;Hamblin, Garrett J;Raymond, Carlee M;Cox, Tyler D;Johnson, Deborah K;Andersen, Joshua L;Weber, K Scott;Bridgewater, Laura C
通讯作者：
Bridgewater, Laura C