Competitive T Lymphocyte Responses to Multiple Antigenic Challenges

描述（由申请人提供）：哺乳动物必须在其一生中与传染病作斗争，在为生存而进行的持续斗争中，如果不能消除病原体，就会导致慢性疾病或死亡，这取决于感染因子。成功消除这些病原体和延长寿命增加了与自发产生的威胁生存的肿瘤作斗争的可能性，除非它们能够被消除。重要的是，与这两个对手的战斗必须经常同时进行，并且受到受影响个人能力的限制。毫无疑问，对对抗传染性病原体和癌症的能力最重要的限制之一是年龄对力量和灵活性的削弱作用。对抗病原体和癌症的责任落在了免疫系统的先天和适应性武器上，它们已经进化到可以强力消除大量的感染因子，也可以像手术一样精确地识别和消除受感染的细胞和癌症。提供这些补充功能的淋巴样细胞在个体生物体内维持着可用的资源，并受到包括年龄、感染史、营养和身心力量等选择性因素的影响。因此，免疫系统必须在限定的范围内发挥作用。淋巴样细胞群之间必然会竞争一般的资源和空间，但个别淋巴细胞群内部也会竞争维持这些特定细胞群的特定功能的信号和细胞因子。T细胞区室内的竞争已被广泛记录，并且幼稚和记忆T细胞亚群都是稳态维持的。与T细胞对病毒的反应相关的短暂扩张和收缩进一步证明了T细胞群体的局限性，其最终结果是记忆细胞频率增加，但群体规模的变化可以忽略不计。响应T细胞群大小的波动提出了一个问题，即如何通过利用已经确立自己为有效应答者的T细胞和新分化且以前未经测试的T细胞，随着时间的推移发展对反复出现的挑战的反应。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致病病毒的反应时，这些潜在的贡献T细胞是如何扩大和发挥作用的。这对长寿人群以及慢性和复发性急性感染的终身目标人群尤为重要。本应用中提出的研究旨在通过实验方法解决这些重要问题，直接评估幼稚T细胞和记忆T细胞在相对中性条件下以及强调T细胞室的功能、多样性和再生能力的条件下对重复抗原挑战维持反应的贡献。

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.