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

基本信息

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
项目类别：
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

项目摘要

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）感染了所有人群，外渗为50-100％，并保持潜在但是，天生和适应性监视。免疫重构和抑制，例如在新生儿和固体器官或造血细胞的受体中移植。经过充分研究，以及响应于HCMV感染和除了这些淋巴细胞外，重新激活还在在HCMV-中观察到了表达NKG2C和其他NK相关受体的TCR CD8 T细胞血清阳性健康供体和患者。针对AML和HCMV感染的细胞，没有针对未感染的同种异体纤维化的活性，并降低了响应CD3刺激的PD-1表达。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细胞转移到年轻人命运的情况下，NKG2C+ CD8 T细胞种群通过 Bcl11b的下调，它改变了TCR信号并促进替代途径有益对于白血病患者，该提案的第一个目的是评估NKG2C+成员的TCELL身份 CD8 T细胞种群（克隆性，TCR特异性和信号传导）以及转录和表观遗传学通过Bcl11b损失从其他CD8 T细胞中改变程序。在NKG2C+ CD8 t -cells上相关的激活和吸入受体，目的是识别您抗肿瘤和抗HCMV活性背后的机制。国际血液和骨髓移植，这是一种广泛的造血细胞移植患者的通畅样本样本将对银行和临床数据库进行研究，以确定是否出现了 NKG2C+ CD8 T细胞种群会影响白血病复发和总体生存的风险在这些研究中，不仅阐明了这种先天的T细胞的治疗潜力，还将阐明如何如何自适应和先天的命运可以桥接。