R01AI194555

TCR-dependent and epigenetic mechanisms guiding influenza-specific CD4+ T cell responses in the lung - Abstract

CD4+ T cells mediate protection from influenza infection in mice and humans and represent a potential target of vaccination.

While influenza-specific T cells may be generated via immunization or viral infection, how the nature of initial antigen exposure shapes the formation, persistence and function of the subsequent CD4+ T cell response to influenza infection is not fully understood.

The long-term objective of our research is to determine the TCR-dependent and epigenetic mechanisms that drive secondary CD4+ T cells responding to influenza infection.

We recently published a collaborative study showing that CD4+ T cell responses to influenza are shaped by prior antigen exposure.

We adopted a sequential heterologous immunization approach in which CD4+ memory T cells generated via either infection or protein immunization are rechallenged with influenza virus.

Both infection- and immunization-induced CD4+ memory T cells undergo extensive secondary expansion following influenza infection, leading to the formation of long-lived and abundant secondary CD4+ memory T cells, both in circulation and in the lung, as well as enhanced germinal center responses.

The function of the secondary response in the lung is guided by the primary challenge.

Primary activation of CD4+ T cells via protein immunization biases the lung CD4 secondary response to influenza towards TFH function, whereas primary CD4+ T cell activation via infection biases the lung CD4 secondary response to influenza towards TH1 function.

Our preliminary data indicate that CD4 effector T cell responses in the lung are also biased towards high TCR signaling and high affinity, as compared to the draining lymph node, suggesting that strong TCR signals may be required to sustain effector responses and drive the formation of large numbers of secondary CD4+ memory T cells.

Additionally, we previously reported that the functional differentiation of CD4+ T cells in response to acute infection is controlled epigenetically by acquisition of DNA methylation programming, with the opposing effects of the DNA methyltransferase DNMT3A and the methylcytosine dioxygenase TET2 determining differentiation outcome and memory T cell plasticity.

Therefore, we will test the overall hypothesis that TCR signal strength and epigenetic DNA methylation programming guide the function and long-term memory of the secondary CD4 T cell response to influenza infection.

Our aims are to:

1) Determine the relationship of TCR signal strength and TCR antigen-binding kinetics, including affinity and bond lifetime under force, to secondary CD4+ T cell differentiation in the lung; and

2) Define the role of TET2- and DNMT3A-dependent epigenetic programming established during primary T cell activation in driving secondary effector function in response to influenza challenge.

University Of Utah

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]

Utah United States

State-Wide

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