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: 10590647
• 负责人: KATHARINE C HSU
• 金额: $ 73.31万
• 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/10590647
• 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; Cytomegalovirus Infections; 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; Preleukemia; 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; 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; terminally differentiated effector memory (TEM) T cells; 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.

项目总结 人巨细胞病毒(HCMV)以50%-100%的外显率感染所有人群，并通过 与生俱来的适应性监视。然而，在以下情况下，它是发病率和死亡率的重要原因 免疫重建和免疫抑制，例如新生儿和固体器官或造血细胞的接受者 移植。经典巨细胞病毒多肽特异性αβ细胞毒T细胞对巨细胞病毒的免疫应答 已经得到了很好的研究，NKG2C+自然杀伤细胞在应对HCMV感染和 重新激活正在积极调查中。然而，除了这些淋巴细胞外，大量的αβ- 在HCMV中也观察到表达NKG2C和其他NK相关受体的TCR CD8 T细胞。 血清阳性的健康捐赠者和患者。这些先天的NKG2C+CD8 T细胞似乎具有广泛的活性 对AML和HCMV感染的细胞，NO对未感染的同种异体成纤维细胞的活性，并降低 CD3刺激后PD-1的表达。RNAseq分析显示NKG2C+CD8 T细胞 降低转录因子Bcl11b的表达，该转录因子对于切断不同的先天命运至关重要 T细胞的早期胸腺发育。这一提议的中心假设是，接触巨细胞病毒会导致 NKG2C+CD8 T细胞群通过将克隆型T细胞转向先天的命运 下调Bcl11b，改变TCR信号并促进有益的替代识别途径 给白血病患者。该提案的第一个目的是评估NKG2C+成员的T细胞身份 CD8T细胞群体(克隆性、TCR特异性和信号)及其转录和表观遗传学 由于Bcl11b的丢失，程序与其他CD8 T细胞不同。第二个目标是评估NK的功能-- NKG2C+CD8T细胞上相关的激活和抑制受体，目的是识别 其抗肿瘤和抗人巨细胞病毒活性背后的机制。最后，在与该中心的合作下 国际血液和骨髓移植--一个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移植后是否出现 NKG2C+CD8T细胞群影响白血病复发风险和总生存期。总之，结果是 这些研究不仅将阐明这种先天T细胞群的治疗潜力，而且还将阐明 适应性的命运和先天的命运是可以沟通的。