Regulation of Naive and Memory T Cell Populations

Mature T cells persist within the body for indefinite periods of time, providing protection from a vast array of pathogens. A fraction of naïve T cells survive for decades and some memory T cells survive for a lifetime without re-exposure to antigen. It is not known how the lifespan of T cells is regulated at the individual, cellular level or at the population level. It is the objective of our research to identify the cellular and molecular interactions regulating the survival of both naïve and memory T cells. This information is crucial to understanding T cell homeostasis and immunological memory (the basis of vaccination against both tumors and pathogens). Several lines of study in our lab aim to identify the molecular signals required to maintain T cells, generate a productive immune response and form long-lived protective immunity. It is our hope that our experiments will improve the understanding of how the immune system recovers following treatment- or illness-induced lymphopenia (such as chemotherapy or HIV infection) and aid in the design of vaccines that provide long-lasting protection from infection. Moreover, by expanding our understanding of how lymphocyte populations are regulated, it will be possible to gain insight into how normal survival signals are co-opted and how homeostatic set points are overcome by cancer cells providing possible targets for therapeutic intervention. Two specific areas of study in our lab are:

The CD8+ T cell response to pathogens

The CD8+ T cell response to intracellular pathogens such as bacteria, viruses and protozoan parasites is an essential component of host resistance. This proposal utilizes experimental infectious disease models of bacteria, Listeria monocytogenes, and Vaccinia virus to address questions about the host CD8+ T cell immune response against potential microbial agents of bioterrorism. We have discovered that E protein transcription-factors and their inhibitors, regulate the CD8+ T cell response to intracellular pathogens, which is a novel function for these proteins. It is our goal to understand at a molecular level how this family of transcriptional regulators influences the activation, proliferation, differentiation and survival of CD8+ T cells as they transition from naïve to effector to memory cells. While the E proteins are known to regulate many key developmental check-points, lineage commitment, proliferation and survival during hematopoiesis and lymphocyte development, the function of these important proteins is unexplored in the mature T cell.

T cell homeostasis

T cells act as antigen-specific sentinels--standing guard, waiting to protect the body in the event of an attack by a pathogen. The peripheral T lymphocyte pool is homeostatically regulated to ensure optimal preparedness. Cell input, proliferation and death are integrated to insure that T cell numbers are maintained at remarkably stable levels throughout adulthood. The subset composition and number of cells within the immune system is very similar for individuals of the same species at the same age suggesting a “hard-wired” mechanism for regulating cell numbers. While many of the cellular and molecular interactions that underlie an active immune response are well characterized, little is understood about the factors that influence homeostasis of T cells in the time before or intervening antigen encounters.

The molecular interactions controlling T cell survival, life span, and compartment size are the focus of our research. Initially, we are focusing on the role of T cell-receptor and IL-7-receptor, two molecules known to be essential for naïve T cells to persist for prolonged periods. We are also studying the differential survival requirements of naïve (antigen-inexperienced) and memory (antigen-experienced) T cells and have identified genes potentially important in the function and survival of memory T cells. Memory lymphocytes sustain the protective immunity obtained following antigen-encounter (infection or vaccination) and are long-lived and self-renewing. Relatively little is known about the molecular interactions that allow the maintenance of this important population. By expanding our understanding of how lymphocyte populations are regulated, it will be possible to gain insight into how normal survival signals are co-opted and how homeostatic set points are overcome by cancer cells. Furthermore, we hope to identify the key mediators of memory T cell longevity to allow better vaccine design.

Funding for our research comes from:

NIH
Cancer Research Institute
Pew Foundation
California Breast Cancer Research Program
V Foundation