Diseases caused by protozoan parasites are major causes of morbidity and mortality throughout the world. Cell-mediated immunity is critical for host defense against these and other medically important intracellular pathogens. Strategies to vaccinate or potentiate cell-mediated immunity have been remarkably ineffective. The difficulty presumably arises from our limited understanding of the mechanisms for establishing and maintaining T lymphocyte memory. This proposal investigates the mechanisms controlling the formation of cellular immunity. Preliminary evidence is offered in support of a model that the molecular signature of type-1 helper T cells is regulated by the hierarchical but overlapping functions of two transcription factors. The sequential action of these two transcription factors appears to be essential for induction of cellular immunity and memory. The experimental approach relies on modeled differentiation systems, and the host response to the protozoan pathogen, Leishmania major. This proposal uses novel genetic approaches, involving conditional gain- and loss-of-functions for transcription factor activity.
The aims are designed to determine how a lineage-restricted gene is induced to progressively higher levels, in order to meet the demands of the microbial burden. The proposal also explores how a cell can transmit its specialized functions to its daughter cells. Finally, the proposal will test the necessity of this intracellular signaling system for immunity and memory against Leishmania major. Successful execution of the 3 specific aims of this proposal should provide new insight into the mechanisms of gene induction and cellular differentiation in an immune response. This information may yield new strategies for preventing and treating parasitic diseases.
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