Competitive T Lymphocyte Responses to Multiple Antigenic Challenges

描述(申请人提供)：哺乳动物必须在其一生中与传染病作持续的斗争，以求生存，如果不能消除病原体，就会导致慢性病或死亡，具体取决于感染源。这些病原体的成功消除和寿命的延长增加了与自发产生的肿瘤作斗争的可能性，这些肿瘤威胁到生存，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，并受到受影响个人能力的限制。毫无疑问，抗击感染性物质和癌症的能力最重要的限制之一是年龄，因为它对力量和灵活性有削弱作用。对抗病原体和癌症的责任落在免疫系统与生俱来的和适应性的手臂上，这些手臂已经进化为野蛮地消除大量的感染性病原体，以及通过手术精确地识别和消除受感染的细胞和癌症。有助于这些互补功能的淋巴细胞在具有可用资源的单个有机体内维持，并受到年龄、感染史、营养以及体力和精神力量等选择性因素的影响。因此，免疫系统必须在规定的限度内发挥作用。必须在淋巴细胞群体之间争夺一般资源和空间，但也必须在单个淋巴细胞群体内部竞争维持这些特定群体的特定信号和细胞因子。T细胞内的竞争已经被广泛地记录下来，幼稚和记忆T细胞亚群都是稳态维持的。T细胞对病毒的短暂扩张和收缩进一步证明了T细胞群体的局限性，最终结果是记忆细胞频率增加，但群体大小变化可以忽略不计。反应T细胞群体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反应者的T细胞和新分化的和以前未检测的T细胞来对反复出现的挑战的反应随着时间的推移而发展。当然，下一个合乎逻辑的问题是，当T细胞隔间被迫维持对其他致病病毒的反应时，这些潜在的贡献T细胞如何扩张和发挥功能。这对长寿的人和慢性和反复发作的急性感染的终生目标尤其重要。本申请中提出的研究旨在通过一种实验方法来解决这些重要问题，以直接评估在相对中性的条件下以及在强调T细胞室的功能、多样性和再生能力的条件下，初始和记忆T细胞在维持对反复抗原挑战的反应中的贡献。 公共卫生相关性：人类一生中对各种传染病和疫苗的免疫反应，个人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多次遇到外来蛋白质如何刺激淋巴细胞的反应，这些淋巴细胞因衰老和对感染的反应而不受限制或受到压力。

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.