Competitive T Lymphocyte Responses to Multiple Antigenic Challenges

T 淋巴细胞对多种抗原挑战的竞争性反应

• 批准号: 8110012
• 负责人: Peter Johnson Wettstein
• 金额: $ 39.03万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110012
• 关键词: Acute; Address; Affect; Affective; Affinity; Age; Aging; Allografting; Antigens; Avidity; Back; Binding; Biological; Biological Assay; CD4 Positive T Lymphocytes; Cancerous; Cells; Cessation of life; Characteristics; Chronic; Chronic Disease; Communicable Diseases; Complementarity Determining Regions; Complex; Cytokine Signaling; DNA Sequence Rearrangement; Dissociation; Ecosystem; Equilibrium; Evolution; Face; Failure; Frequencies; Genes; Habitats; Helper-Inducer T-Lymphocyte; Human; Immune system; Immunoglobulin Joining Region; Individual; Infection; Infectious Agent; Knowledge; Lead; Left; Life; Longevity; Lymphocyte; Lymphoid; Lymphoid Cell; Maintenance; Major Histocompatibility Complex; Major Histocompatibility Complex Gene; Malignant Neoplasms; Mammals; Memory; Minor Histocompatibility Antigens; Nucleotides; Organism; Output; Peptides; Play; Population; Population Sizes; Probability; Proteins; Psyche structure; Recording of previous events; Recruitment Activity; Recurrence; Reproduction; Resources; Role; Series; Skin graft; Specificity; Stimulus; Stress; System; T cell response; T memory cell; T-Cell Antigen Receptor Specificity; T-Cell Receptor; T-Lymphocyte; Testing; Thymectomy; Time; Transcript; Vaccination; Variant; Virus; Virus Diseases; Wages; age effect; age related; antigen challenge; arm; base; beta Chain Antigen T Cell Receptor; cancer cell; combat; cytotoxic; environmental change; falls; fighting; flexibility; immunogenic; mouse model; novel; nutrition; pathogen; public health relevance; regenerative; research study; response; tumor; variable region gene

DESCRIPTION (provided by applicant): Mammals must combat infectious diseases throughout their entire lives in continuous fights for survival where failure to eliminate pathogens results in either chronic disease or death, depending on the infectious agent. Successful elimination of these pathogens and increased longevity increase the probability of combating spontaneously arising tumors that threaten survival unless they can be eliminated. Importantly, battles against these two adversaries must often be waged simultaneously and are limited by the capabilities of the affected individuals. Without question, one of the most important limitations on the ability to fight infectious agents and cancer is age with its debilitating effects on strength and flexibility. The responsibility for fighting pathogens and cancer falls to the innate and adaptive arms of the immune system which have evolved for the brute-force elimination of large numbers of infectious agents as well as the surgically precise identification and elimination of infected cells and cancers. Lymphoid cells that contribute these complementary functions are maintained within individual organisms with the resources that are available and that are affected by selective factors including age, history of infections, nutrition, and physical and mental strength. Therefore, the immune system must function within defined limitations. Competition must occur between populations of lymphoid cells for general resources and space but also within individual lymphocyte populations for signals and cytokines that are specific for maintenance and functions of those specific populations. Competition within the T cell compartment has been extensively documented, and both naive and memory T cell subpopulations are homeostatically maintained. The limits of T cell populations are further exemplified by the transient expansions and contractions associated with T cell responses to viruses where the end result is increased memory cell frequencies but negligible changes in population size. The fluctuations in sizes of responding T cell populations raise the question as to how the responses to recurring challenges develop over time through utilization of T cells that have already established themselves as effective responders and T cells that are newly differentiated and previously untested. Of course, the next logical question asks how these potentially contributing T cells expand and function when the T cell compartment is forced to sustain responses to other pathogenic viruses. This is particularly important for humans who are long-lived and the life-long targets of chronic and recurring acute infections. The studies proposed in this application are aimed at addressing these important issues with an experimental approach to directly evaluate the contributions of naive and memory T cells in sustaining responses to repeated antigenic challenges under relatively neutral conditions as well as conditions that stress the function, diversity, and regenerative capacity of the T cell compartment. PUBLIC HEALTH RELEVANCE: Humans immunologically respond to a wide variety of infectious diseases and vaccinations throughout their lives, and the abilities of individuals to respond to these stimuli are affective by selective factors that include age and history of infections. The experiments presented in this application are aimed at understanding how multiple encounters with foreign proteins stimulate responses of lymphocytes that are either unrestrained or stressed by aging and responses to infections.

描述（由申请人提供）：哺乳动物必须在其整个生命中与传染病作斗争，不断为生存而战，如果未能消除病原体，则会导致慢性疾病或死亡，具体取决于传染源。成功消除这些病原体和延长寿命增加了对抗自发产生的肿瘤的可能性，除非它们可以被消除，否则这些肿瘤会威胁生存。重要的是，与这两个对手的战斗往往必须同时进行，并且受到受影响个人能力的限制。毫无疑问，对抗传染性病原体和癌症的能力的最重要限制之一是年龄及其对力量和灵活性的削弱作用。对抗病原体和癌症的责任福尔斯落在免疫系统的先天性和适应性武器上，它们已经进化为蛮力消除大量感染因子以及手术精确识别和消除感染细胞和癌症。贡献这些互补功能的类肉瘤细胞维持在具有可用资源的个体生物体内，并且受到选择性因素的影响，包括年龄，感染史，营养以及身体和精神力量。因此，免疫系统必须在限定的范围内发挥作用。竞争必须发生在淋巴细胞群体之间的一般资源和空间，但也在单个淋巴细胞群体内的信号和细胞因子，是特定的维护和功能的这些特定群体。T细胞区室内的竞争已被广泛记录，并且初始和记忆T细胞亚群均被稳态维持。T细胞群体的局限性进一步通过与T细胞对病毒的应答相关的瞬时扩增和收缩来举例说明，其中最终结果是记忆细胞频率增加，但群体大小的变化可以忽略不计。应答T细胞群体的大小波动提出了一个问题，即通过利用已经确立自身为有效应答者的T细胞和新分化且先前未经测试的T细胞，对反复出现的挑战的应答如何随时间发展。当然，下一个合乎逻辑的问题是，当T细胞区室被迫维持对其他病原性病毒的反应时，这些潜在的贡献T细胞如何扩增和发挥作用。这对于长寿的人以及慢性和复发性急性感染的终身目标尤为重要。本申请中提出的研究旨在用实验方法解决这些重要问题，以直接评价初始和记忆T细胞在相对中性条件下以及在强调T细胞区室的功能、多样性和再生能力的条件下对重复抗原挑战的持续应答的贡献。 公共卫生相关性：人类在一生中对各种各样的传染病和疫苗接种产生免疫反应，个体对这些刺激的反应能力受到包括年龄和感染史在内的选择性因素的影响。本申请中提出的实验旨在了解与外源蛋白的多次接触如何刺激淋巴细胞的反应，这些淋巴细胞要么不受限制，要么受到老化和感染反应的影响。