Gamma delta T cells and human wound healing

描述(由申请人提供)：一系列复杂的事件是有效愈合人体伤口所必需的。人的表皮和真皮中存在大量的γ-β和α-βT细胞，但这些T细胞在创面愈合中的作用尚未得到研究。我们已经确定，缺乏皮肤伽马德尔塔T细胞的小鼠在角质形成细胞增殖、组织再上皮化和创伤后炎症方面存在缺陷。这增加了这样一种可能性，即皮肤伽马增量T细胞产生特定的生长因子、趋化因子和其他因子可能是有效的人类伤口愈合的关键。我们的假设是，皮肤上皮内α-β和γ-βT细胞群与迁移到创面的循环T细胞之间存在功能差异。我们假设，皮肤驻留的T细胞识别受损角质形成细胞表达的抗原，刺激产生直接启动伤口修复的因子，并调节邻近细胞的功能，并将浸润性细胞定向到损伤部位。这些皮肤T细胞的缺失或功能异常会影响修复，并可能导致延迟愈合和无法愈合的伤口。慢性无法愈合的伤口对病人的健康和医疗保健系统的成本有重大影响。烧伤创面愈合延迟会导致热损伤患者的发病率和随后的死亡率。这些研究的目的是调查上皮细胞驻留的人类皮肤T细胞在伤口愈合中的作用。我们已经在临床医生和基础科学家之间建立了一个合作关系，以确定驻留在人类皮肤中的T细胞是否参与了有效的伤口愈合。我们将确定皮肤T细胞在伤口愈合中的作用机制，并确定这些功能是否是皮肤常驻T细胞所独有的。我们将确定在未愈合的伤口中皮肤驻留的T细胞是否功能失调，以及这些缺陷的机制。最后，我们将确定激活的皮肤驻留T细胞是否可以加速或恢复延迟的伤口愈合。如果慢性或不可愈合伤口中的T细胞有缺陷，将测试新的策略，以确定恢复正常、功能正常的T细胞是否会改善或加速伤口愈合。与公共卫生相关：在美国，超过400万患者患有慢性伤口，这导致了发病率和死亡率。拟议的研究将提供对皮肤驻留T细胞在伤口愈合中的功能的更多了解，结果将确定利用这些细胞开发治疗不可愈合伤口的新策略的临床潜力。

DESCRIPTION (provided by applicant): A complex series of events are necessary for effective healing of human wounds. There are resident populations of gamma delta and alpha beta T cells in human epidermis and dermis, but the role of these T cells in wound healing has not been examined. We have determined that mice lacking skin gamma delta T cells have defects in keratinocyte proliferation, tissue reepithelialization, and inflammation following wounding. This raises the possibility that skin gamma delta T cell production of specific growth factors, chemokines, and other factors may be critical for effective human wound healing. Our hypothesis is that there are functional differences between the skin-resident intraepithelial alpha beta and gamma delta T cell populations and the circulating T cells that migrate into wounds. We hypothesize that skin-resident T cell recognition of antigen expressed by injured keratinocytes stimulates production of factors which directly initiate wound repair as well as modulate function of neighboring cells and direct infiltrating cells to sites of damage. The absence or aberrant function of these skin-resident T cells would impact repair and may contribute to delayed healing and non-healing wounds. Chronic non-healing wounds have a significant impact on patient well being and on costs to the health care system. Delayed healing of burn wounds contribute to morbidity and subsequent mortality of thermally injured patients. The goal of these studies is to investigate the role of epithelial-resident human skin T cells in wound healing. We have established a collaboration between clinicians and basic scientists to determine if T cells that are resident in human skin participate in effective wound healing. We will determine the mechanisms of skin T cell function in wound healing and determine if these functions are unique to skin-resident T cells. We will determine if skin-resident T cells are dysfunctional in non-healing wounds and the mechanisms of the defects. Finally we will determine if activated skin-resident T cells can accelerate or restore delayed wound healing. If T cells are defective in chronic or non-healing wounds, new strategies will be tested to determine if restoration of normal, functional T cells will improve or accelerate wound healing. PUBLIC HEALTH RELEVANCE: Over 4 million patients in the U.S. are afflicted with chronic wounds that contribute to morbidity and mortality. The proposed studies should provide a greater understanding of the functions of skin- resident T cells in wound healing and results will determine the clinical potential of exploiting these cells to develop new strategies for treatment of non-healing wounds.