The extraordinary complexity of the mammalian immune system, a distributed network of organs, tissues, cells and extracellular factors maintained in a dynamic equilibrium, offers numerous conceptual and practical challenges but also the promise of improved prophylactic and therapeutic modalities for many common diseases. My laboratory is primarily interested in the generation, perpetuation and regulation of immunological memory, autoimmunity and persistent viral disease, wide-ranging areas of investigation that are nevertheless united by our focus on T cells as both guardians and adversaries of health and well-being. Our work seeks to identify and elucidate the distinctive properties of specific T cell populations that provide protection upon re-encounter with a pathogen (T cell memory), cause defined damage (autoimmunity), or are impaired in their capacity to control an infection (persistent viral disease). Despite the fundamentally different consequences for health and disease in these experimental and naturally occurring scenarios, the generation of protective, destructive or ineffectual T cell responses is apparently governed by the distinct balance of shared molecular interactions a more detailed understanding of which will inform the development of novel therapeutic approaches that aim to variously embellish or curtail specific T cell responses.
The Good: T cell memory. One of the most striking attributes of immune system is the phenomenon of immunological memory, the basis for enhanced protection against disease upon re-exposure to previously encountered pathogens and the efficacy of vaccination as a tool for global control of infectious diseases. Although specific antibody titers often correlate well with protective immunity, control of most viral and many bacterial infections requires the participation of T cells. Our current work on the generation and long-term preservation of pathogen-specific T cell memory includes an investigation into the unexpectedly beneficial consequences of memory T cell aging (and the development of a novel model for T cell memory in general), the regulation of T cell immunity by extracellular adenosine generation and signaling, the role of hypoxia-inducible factors (HIFs) in pathogen-specific T cell immunity, and the function of T cell-produced chemokines in the orchestration of protective immune responses.
The Bad: Autoimmunity. Among the autoimmune diseases that affect an estimated 3% of the US population, type 1 diabetes (T1D) constitutes one of the most prominent conditions and poses significant challenges to afflicted individuals, to the development of effective therapeutic interventions and to public health initiatives at large. While the complex interactions between inherited susceptibilities and environmental factors that together trigger T1D remain to be elucidated in detail, specific T cells are the cardinal effectors of disease in both mouse and man. These T cells recognize and destroy insulin-secreting beta-cells in the pancreas leading to elevated blood sugar levels and serious disturbances of protein, fat and carbohydrate metabolism. The coordination of destructive T cell immunity is in part regulated by chemokines, and our T1D-related projects are focused on selected chemokines and their receptors as critical components of for T1D pathogenesis and potential targets for therapeutic intervention.
The Ugly: Persistent viral disease. Chronic viral infections continue to present major public health problems and pose a particular challenge to the immune system. Failure to effectively control infections with viruses such as HIV, CMV, EBV or hepatitis B and C results in the persistence of virus, viral proteins or genes that may coexist indefinitely in the presence of an immune response that can be impaired to varying degrees. At present, we are especially interested in identifying cardinal components of virus-specific T cells required for eventual control of persistent infections, and in the development of therapeutic approaches that potentiate antiviral T cell immunity by combining the blockade of inhibitory pathways with the selective stimulation of T cell subsets using antibody-cytokine immune complexes.