Interface of memory CD4 T cells and innate immunity in viral response

病毒反应中记忆 CD4 T 细胞与先天免疫的界面

• 批准号: 8665103
• 负责人: SUSAN L SWAIN
• 金额: $ 47.77万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 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/8665103
• 关键词: Acute; Affinity; Agonist; Antibodies; Antibody Formation; Antigens; Automobile Driving; B-Lymphocytes; Blood; CD4 Positive T Lymphocytes; Cells; Collaborations; Complement; Core Protein; Cross Reactions; Effector Cell; Elements; Epitopes; Gene Expression; Human; Human Herpesvirus 6; ITGAX gene; Immune; Immunity; Infection; Inflammation Mediators; Inflammatory Response; Inflammatory Response Pathway; Influenza; Influenza A virus; Kinetics; Knowledge; Learning; Life; Location; Lung; Lymphocytic choriomeningitis virus; Mediating; Memory; Memory B-Lymphocyte; Modeling; Molecular; Mus; Mutate; NK Cell Activation; Natural Immunity; Natural Killer Cells; Nature; Pathology; Pathway interactions; Pattern; Peptides; Plasma Cells; Play; Production; Proteins; RNA Viruses; Recruitment Activity; Regulation; Resistance; Role; Seasons; Stimulus; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Translations; Vaccine Adjuvant; Vaccines; Viral; Viral Load result; Viral Physiology; Virus; Virus Diseases; adaptive immunity; cytokine; design; immunopathology; in vitro Model; insight; killings; memory CD4 T lymphocyte; model development; neutralizing antibody; pathogen; programs; protective efficacy; respiratory; response

Current vaccines to influenza and other RNA viruses have been designed to generate neutralizing antibodies (Ab), but cannot protect against new strains that arise each year and evade Ab from previous seasons. CD4 memory cells, however, respond to elements of the virus that do not change, but current vaccines have not been designed to optimize CD4 memory and the memory cells do not persist as long as antibody. Thus our focus is to define the potential of CD4 memory to provide immunity and to learn which subsets are needed and how they act. Our studies have shown that CD4 memory cells elicit innate responses when challenged even without live pathogen or pathogen components and we suggest that they may therefore act to enhance immunity without the need for the stimulus provided by live virus. We have shown that they can protect against live virus by activating innate cell NK cells and B cells, and thus may be able to generate robust immunity to new viral pathogens and enhance long-term B cell memory. The mechanisms leading to NK induction are little known. With our collaborators in the program, we will analyze the mechanisms by which the various subsets of CD4 memory: 1) interact with innate NK cells; 2) provide help for B cells in influenza and LCMV virus models and participate in heterosubtypic (response to different strain) and cross-reactive immunity and we will determine if memory cells can substitute for, or complement, the pathogen recognition pathways either induced by live virus or vaccine adjuvants in inducing NK cell activation. We will analyze the mechanisms involved in these CD4 helper activities. We will determine whether the memory cells have more potent activity because they are resistant to NK mediated killing and 3) we will examine these same CD4 memory responses in humans in collaboration with Project 4. We believe these studies will provide important insights into the potential of CD4 memory induction by vaccines that can provide superior immunity to respiratory pathogens while avoiding irnmunopathdiogy.

目前针对流感和其他RNA病毒的疫苗被设计为产生中和抗体（Ab），但不能保护每年出现的新毒株，也不能逃避前几个季节的Ab。然而，CD 4记忆细胞对病毒的不改变的元素作出反应，但目前的疫苗还没有被设计成优化CD 4记忆，并且记忆细胞不像抗体那样持久。因此，我们的重点是确定CD 4记忆提供免疫力的潜力，并了解需要哪些亚群以及它们如何发挥作用。我们的研究表明，即使没有活病原体或病原体成分，CD 4记忆细胞在受到挑战时也会引发先天性反应，因此我们认为它们可能在不需要活病毒提供刺激的情况下发挥增强免疫力的作用。我们已经证明，它们可以通过激活先天性NK细胞和B细胞来抵御活病毒，因此可能能够对新的病毒病原体产生强大的免疫力，并增强长期B细胞记忆。导致NK诱导的机制知之甚少。与我们的合作者一起，我们将分析CD 4记忆的各种亚群的机制：1）与先天NK细胞相互作用; 2）为流感和LCMV病毒模型中的B细胞提供帮助，并参与异亚型（对不同菌株的反应）和交叉反应性免疫，我们将确定记忆细胞是否可以替代，或补充，在诱导NK细胞活化中，由活病毒或疫苗佐剂诱导的病原体识别途径。我们将分析参与这些CD 4辅助活动的机制。我们将确定记忆细胞是否具有更有效的活性，因为它们对NK介导的杀伤具有抗性; 3）我们将与项目4合作，在人类中检查这些相同的CD 4记忆反应。我们相信，这些研究将为疫苗诱导CD 4记忆的潜力提供重要的见解，这些疫苗可以提供对呼吸道病原体的上级免疫，同时避免免疫病理学。