Aspergillus-specific CD4+ T cells in Invasive Aspergillosis

描述（由申请人提供）：烟曲霉是临床上重要的真菌病原体，可引起免疫功能低下宿主的侵袭性疾病。接受高强度化疗方案的白血病患者和骨髓移植患者患侵袭性曲霉病（IA）的风险特别高，相关死亡率约为90%。在IA小鼠模型中的研究表明，曲霉特异性分泌ifn - γ的T淋巴细胞通过限制侵袭性真菌疾病发挥保护作用，而产生IL-4和IL-13的T细胞具有有害作用。尽管这些研究清楚地表明CD4 T细胞影响烟曲霉感染的结果，但许多决定T细胞活化和募集的因素仍然不明确。此外，曲霉特异性CD4 T细胞是否能介导既定疾病的解决仍有待确定。为了开始解决这些问题，候选人Amariliz Rivera博士克隆了烟曲霉特异性的CD4 T细胞，分离了T细胞受体（TCR）抗原特异性α和β链的编码基因，并产生了TCR转基因小鼠。初步结果表明，这些小鼠表达了识别烟曲霉菌丝的功能性TCR。单克隆曲霉特异性CD4 T细胞的可用性将为候选人提供独特的机会，以实现以下目标：1)表征CD4 T细胞对吸入烟曲霉孢子的激活和分化反应，2)确定调节细胞因子IL-10和tgf β在这一过程中的作用，3)检查并发先天炎症反应对T细胞激活的影响，4)确定烟曲霉特异性T细胞是否具有IA保护作用。此外，这些研究将为CD4 T细胞对抗癌症患者真菌感染的潜在治疗用途奠定基础。Rivera博士将在纪念斯隆凯特琳癌症中心的Eric G. Pamer博士的指导下进行这些研究。通过这个K01奖项，候选人将获得成功竞争独立教师职位所需的技能和经验。作为一名波多黎各裔女性，这位候选人将努力成为年轻的西班牙裔科学家的杰出榜样。

DESCRIPTION (provided by applicant): Aspergillus fumigatus is a clinically important fungal pathogen that causes invasive disease in immunocompromised hosts. Leukemia patients receiving intense chemotherapy regimens and bone marrow transplanted patients are particularly at risk for Invasive Aspergillosis (IA) with an associated mortality rate of approximately 90%. Studies in mouse models of IA have suggested that Aspergillus-specific IFN-gamma secreting T lymphocytes play a protective role by limiting invasive fungal disease while IL-4 and IL-13 producing T cells have a deleterious impact. Although it is clear from these studies that CD4 T cells influence the outcome of A. fumigatus infection, many of the factors that determine T cell activation and recruitment remain poorly defined. Moreover, it remains to be determined whether Aspergillus-specific CD4 T cells can mediate the resolution of established disease. In order to begin to address these questions, the candidate, Dr. Amariliz Rivera, cloned CD4 T cells specific for A. fumigatus, isolated the genes encoding the antigen specific alpha and beta chains of the T cell receptor (TCR) and generated TCR transgenic mice. Preliminary results demonstrate that these mice express a functional TCR that recognizes A. fumigatus hyphae. The availability of monoclonal Aspergillus-specific CD4 T cells will give the candidate the unique opportunity to address the following aims: 1) to characterize the activation and differentiation of CD4 T cell responses to inhaled A. fumigatus spores, 2) to establish the role of the regulatory cytokines IL-10 and TGFbeta in this process, 3) to examine the influence of concurrent innate inflammatory responses on T cell activation and 4) to establish whether A. fumigatus-specific T cells can confer protection from IA. Furthermore, these studies will establish the foundation for the potential therapeutic use of CD4 T cells against fungal infections in the cancer patient. Dr. Rivera will perform these studies under the guidance of Dr. Eric G. Pamer at Memorial Sloan Kettering Cancer Center. Through this K01 award the candidate will gain the skills and experience necessary to successfully compete for an independent faculty position. As a woman of Puerto Rican descent the candidate will strive to be an outstanding role model for younger Hispanic scientists.