HCMV-induced innate-like CD8 T cells and allogeneic HCT outcome

HCMV 诱导的先天样 CD8 T 细胞和同种异体 HCT 结果

• 批准号: 10390447
• 负责人: KATHARINE C HSU
• 金额: $ 70.98万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-09 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10390447
• 关键词: Acute Myelocytic Leukemia; Adopted; Allogenic; Blood; Bone Marrow Transplantation; CD28 gene; CD3 Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Line; Cell Therapy; Cells; Clonality; Collaborations; Cytomegalovirus; Cytotoxic T-Lymphocytes; Development; Down-Regulation; Dysmyelopoietic Syndromes; Epigenetic Process; Event; Exhibits; Exposure to; Fibroblasts; Gene Expression Profile; Genetic; Genetic Transcription; Goals; Human; Immune; Immune response; Immunologic Surveillance; Immunosuppression; In Vitro; Individual; Infection; Investigation; KLRD1 gene; Leprosy; Leukocytes; Link; Lymphocyte; Lymphoid; Lymphoid Cell; Malignant Neoplasms; Measurable; Measures; Memory; Molecular; Morbidity - disease rate; Natural Killer Cells; Organ; Outcome; Pathway interactions; Patients; Penetrance; Peptides; Phenotype; Population; Relapse; Risk; Sampling; Signal Transduction; Solid; Source; Specificity; Surface; T cell response; T-Cell Development; T-Lymphocyte; Therapeutic; Thymus Gland; Transplant Recipients; Viral; Viral Physiology; Virus; Virus Diseases; acute myeloid leukemia cell; alpha-beta T-Cell Receptor; beneficiary; cancer cell; clinical database; curative treatments; cytotoxic; hematopoietic cell transplantation; immune reconstitution; imprint; international center; leukemia; leukemia relapse; member; mortality; neonate; pathogen; post-transplant; programmed cell death protein 1; programs; receptor; recruit; response; seropositive; transcription factor; transcriptome sequencing; tumor; γδ T cells

PROJECT SUMMARY Human cytomegalovirus (HCMV) infects all populations with a penetrance of 50-100% and is kept latent by innate and adaptive surveillance. However, it is a significant cause of morbidity and mortality in conditions of immune reconstitution and suppression, such as in neonates and recipients of solid organ or hematopoietic cell transplants. The T cell response to HCMV through classical HCMV peptide-specific αβ cytotoxic T lymphocytes has been well-studied, and the development of NKG2C+ natural killer cells in response to HCMV infection and reactivation is under active investigation. In addition to these lymphocytes, however, large populations of αβ- TCR CD8 T cells that express NKG2C and other NK-associated receptors have also been observed in HCMV- seropositive healthy donors and patients. These innate-like NKG2C+ CD8 T cells appear to have broad activity against AML and HCMV-infected cells, no activity against uninfected allogeneic fibroblasts, and reduced expression of PD-1 in response to CD3 stimulation. RNAseq analysis has revealed that NKG2C+ CD8 T cells have reduced expression of the transcription factor Bcl11b, critical for cutting off alternative innate fates during the early thymic development of T cells. The central hypothesis of this proposal is that HCMV exposure induces an NKG2C+ CD8 T cell population by diverting clonotypic T cells toward an innate fate through the downregulation of Bcl11b, which alters TCR signaling and promotes alternative recognition pathways beneficial to leukemia patients. The first aim of the proposal is to evaluate the T cell identity of members of the NKG2C+ CD8 T cell population (clonality, TCR specificity and signaling) and how their transcriptional and epigenetic programs are altered from other CD8 T cells by Bcl11b loss. The second aim will assess the function of the NK- associated activating and inhibitory receptors on the NKG2C+ CD8 T cells, with the goal of identifying the mechanism behind their anti-tumor and anti-HCMV activity. Finally, in a collaboration with the Center for International Blood and Marrow Transplantation, an extensive hematopoietic cell transplantation patient sample bank and clinical database will be utilized to determine whether the post-transplantation emergence of an NKG2C+ CD8 T cell population impacts the risk of leukemia relapse and overall survival. Together, the results of these studies will elucidate not only the therapeutic potentials of this innate-like T cell population but also how adaptive and innate fates can be bridged.

项目摘要 人类巨细胞病毒（HCMV）感染所有人群的外观为50-100％，并保持潜在 先天和适应性监视。但是，这是导致发病率和死亡率的重要原因 免疫重建和抑制，例如在固体器官或造血细胞的新生儿和受体中 移植。 T细胞通过经典的HCMV肽特异性αβ细胞毒性T淋巴细胞的T细胞反应 经过充分研究，以及响应于HCMV感染和 重新激活正在积极投资。但是，除了这些淋巴细胞外，大量的αβ-种群 在HCMV-中也观察到了表达NKG2C和其他NK相关受体的TCR CD8 T细胞 血清反应健康的供体和患者。这些先天的NKG2C+ CD8 T细胞似乎具有广泛的活性 针对AML和HCMV感染的细胞，对未感染的同种异体成纤维细胞无活性，并减少 PD-1响应CD3刺激的表达。 RNASEQ分析表明NKG2C+ CD8 T细胞 降低了转录因子Bcl11b的表达，对于切断替代的先天命运至关重要 T细胞的早期胸腺发育。该提议的中心假设是HCMV暴露会诱导 通过将clonotypic T细胞转移到先天命运的NKG2C+ CD8 T细胞种群中 Bcl11b的下调，它改变了TCR信号并促进替代识别途径有益 致白血病患者。该提案的第一个目的是评估NKG2C+成员的T细胞身份 CD8 T细胞种群（克隆性，TCR特异性和信号传导）以及它们的转录和表观遗传如何 通过BCL11B丢失从其他CD8 T细胞中改变程序。第二个目标将评估NK-的功能 在NKG2C+ CD8 T细胞上相关的激活和抑制受体，目的是确定 其抗肿瘤和抗HCMV活性的机制。最后，与中心合作 国际血液和骨髓移植，一种广泛的造血细胞移植患者样本 将利用银行和临床数据库来确定转移后出现是否存在 NKG2C+ CD8 T细胞群会影响白血病继电器和总体生存的风险。一起，结果 在这些研究中，不仅阐明了这种先天的T细胞种群的治疗潜力，还将阐明如何阐明 自适应和先天的命运可以桥接。