R01AI150999

HCMV-Induced Innate-Like CD8 T Cells and Allogeneic HCT Outcome - 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 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 antigen-specific 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.

Sloan-Kettering Institute For Cancer Research

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

New York, New York 100656007 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 374% from $759,700 to $3,601,018.