R01AI153363

Determinants of Differentiation and Maintenance of PD-1+ CD8 T Cells - Summary

Recent findings have identified that programmed cell death (PD)-1+ CD8 T cells recognizing tumor or chronic pathogens have a division of labor: T cell factor (TCF)-1+ PD-1+ CD8 T cells function as memory-like resource cells, while TCF-1neg PD-1+ CD8 T cells have effector-like function. TCF-1+ PD-1+ CD8 T cells self-renew and differentiate into effector-like and terminally differentiated/more exhausted TCF-1neg PD-1+ CD8 T cells.

TCF-1+ memory-like cells have high expression of CD28, and it has been shown that during PD-1 targeted therapies, CD28 costimulation is required for the reinvigoration of CD8 T cell responses. Additionally, memory-like cells have high expression of ICOS and a gene expression program with similarities to follicular helper CD4 T cells. Preliminary data suggests that during established chronic lymphocytic choriomeningitis virus (LCMV) infection, continuous CD28 signaling is required for differentiation and self-renewal of TCF-1+ memory-like PD-1+ CD8 T cells. In contrast, ICOS signaling diminishes differentiation into effector-like cells. The mechanisms by which memory-like cells choose between self-renewal and differentiation, as well as how to modulate differentiation into effector-like cells, are critical questions.

In addition to a unique set of costimulatory molecules, TCF-1+ memory-like cells also express a distinct set of chemokine/cytokine receptors. Based on these data and the knowledge gap in the field, we propose to define the role of costimulation in the maintenance and differentiation of PD-1+ CD8 T cells (Aim 1) and uncover the impact of cellular interactions (Aim 2). In Aim 1, we will determine how CD28 and ICOS costimulation affect TCF-1+ memory-like PD-1+ CD8 T cells and identify transcriptional regulators of T cell fate. In Aim 2, we will use an unbiased approach to identify cellular interactions of TCF-1+ memory-like PD-1+ CD8 T cells in vivo and probe the biological consequences of these interactions for T cell fate decisions.

XCL-1, a chemoattractant for XCR1+ dendritic cells (DC1), is highly expressed by TCF-1+ memory-like cells and modulated by CD28 signaling. We will address the role of DC1 antigen presentation and XCL-1 production on the localization, differentiation, and self-renewal of TCF-1+ memory-like PD-1+ CD8 T cells. Understanding the determinants of self-renewal and differentiation of T cells chronically exposed to antigens would have broad implications for immunotherapies in many pathologies, including chronic infections, cancer, autoimmunity, transplantation, and allergy.

Icahn School Of Medicine At Mount Sinai

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 100296504 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 399% from $653,982 to $3,265,402.