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.

项目概要 人类巨细胞病毒（HCMV）以 50-100% 的外显率感染所有人群，并通过以下方式保持潜伏状态： 先天性和适应性监视。然而，它是在以下情况下发病和死亡的一个重要原因： 免疫重建和抑制，例如新生儿和实体器官或造血细胞的接受者 移植。 T 细胞通过经典 HCMV 肽特异性 αβ 细胞毒性 T 淋巴细胞对 HCMV 做出反应 已得到充分研究，NKG2C+ 自然杀伤细胞响应 HCMV 感染和 重新激活正在积极调查中。然而，除了这些淋巴细胞之外，还有大量的 αβ- 表达 NKG2C 和其他 NK 相关受体的 TCR CD8 T 细胞也在 HCMV- 血清反应呈阳性的健康捐献者和患者。这些先天性 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没有活性，并减少 CD3刺激后PD-1的表达。 RNAseq 分析表明 NKG2C+ CD8 T 细胞 转录因子 Bcl11b 的表达减少，这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。该提案的中心假设是 HCMV 暴露会诱发 通过将克隆型 T 细胞转向先天命运，NKG2C+ CD8 T 细胞群 Bcl11b 下调，改变 TCR 信号传导并促进替代识别途径，有益 给白血病患者。该提案的第一个目标是评估 NKG2C+ 成员的 T 细胞身份 CD8 T 细胞群（克隆性、TCR 特异性和信号传导）及其转录和表观遗传 由于 Bcl11b 缺失，其他 CD8 T 细胞的程序发生了改变。第二个目标是评估 NK 的功能 NKG2C+ CD8 T 细胞上相关的激活和抑制受体，目的是识别 其抗肿瘤和抗 HCMV 活性背后的机制。最后，与中心合作 国际血液和骨髓移植，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+ CD8 T 细胞群影响白血病复发和总体生存的风险。综合起来，结果 这些研究不仅将阐明这种先天性 T 细胞群的治疗潜力，还将阐明如何 适应性命运和先天命运是可以弥合的。