My lab is interested in immunological memory, autoimmunity and persistent viral disease. The common theme among these topics is a focus on T cell immunity under conditions where specific T cells provide protection upon reencounter with a pathogen (T cell memory), may cause pathology (autoimmunity), or are impaired in their capacity to control an infection (persistent viral disease). These areas are further united by an experimental approach that aims to assure the pertinence of research endeavors by balancing an appropriate systemic complexity with the feasibility to analyze and manipulate T cell immunity in detail. The experimental system used in the majority of our studies employ "natural" host-pathogen interactions with an experimental emphasis on identification, characterization, localization, isolation and manipulation of specific T cells.

1. T cell memory: Among the most striking attributes of adaptive immunity 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.

T cell memory is an active process that regulates the preservation of specific memory T cell populations in a dynamic environment. As such, specific memory T cells are subject to a dynamic balance between A. cellular longevity and programmed death (apoptosis), B. gradual maturation and age-associated impairments (senescence), C. rest and proliferative self-renewal (homeostatic proliferation) as well as D. tissue residence and migration. Our work aims to understand the phenomenology and mechanistic foundation of this balance by studying the generation, regulation and preservation of T cell immunity in response to selected viruses (lymphocytic choriomeningitis virus [LCMV], vesicular stomatitis virus [VSV] and others) and bacteria. Current projects include the identification and characterization of cytokines involved in the differential regulation of specific CD4+ and CD8+ T cell memory as well as a study of the extended maturation process of established T cell memory.

2. Autoimmunity: Despite its common association with autoimmune diseases (which affect an estimated 3% of the US population), autoimmunity is a more general phenomenon that also has a physiological component and may even be harnessed for therapeutic purposes. Our lab explores the juncture of destructive and protective autoimmunity in models of type 1 diabetes (T1D) to define parameters of pathogenesis and to evaluate strategies for immunotherapeutical intervention. In our previous work, we have analyzed the potential for induction of self-antigen-specific "regulatory" T cells (TREG) and their interaction with diabetogenic T cells as well as antigen-presenting cells (APC).

Currently, we are evaluating the feasibility to adapt lentivirus-based RNA interference (RNAi) to the study of T1D pathogenesis. The aim of this project is the systematic analysis of diabetogenic T cells specific for defined target (β-cell) antigens. We expect that this approach will provide a rapid and convenient method to define essential characteristics of destructive T cell activity and identify targets for therapeutic intervention in the course of progressive autoimmune disease.

3. 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. The precise balance between persisting virus and immune response depends on multiple factors such as nature of the infecting virus, route of infection and initial viral burden as well as the immune status of the infected host. The interplay between these parameters ultimately determines the spectrum of possible clinical symptoms associated with viral disease. Using the LCMV system, we are developing projects to further investigate the impact of permanent or protracted viral persistence on the generation and maintenance of heterologous and homologous T cell immunity. We are also planning to study the role of viral persistence in promotion or prevention of autoimmune diabetes.

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