Molecular mechanisms and function of P2X7 ion channel gating on T cells

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P2X7 is a nucleotide-gated ion channel that plays an important role in inflammation. The primary goal of the proposed project is to elucidate the molecular mechanisms and functions of P2X7 ion channel gating on T cells. To this end, we have generated nanobodies (single domain antibodies from immunized llamas) that effectively block or potentiate gating of P2X7 by extracellular nucleotides. These nanobodies provide unique tools to assess the expression of P2X7 and to modulate the function of P2X7 on murine and human cells during immune responses. We will use P2X7 mutants and chimeras to determine the amino acid residues of P2X7 important for nanobody binding and for gating of the receptor. We will evaluate the therapeutic potential of the nanobodies in experimental inflammation in two mouse models. We expect our studies to yield a better understanding of the role of P2X7 in physiological and pathological immune responses. We will characterize P2X7 expression and function in human T cells and use our P2X7-specific nanobodies to modulate T cell effector functions. The results are expected to provide a basis for therapeutical applications of P2X7-specific nanobodies. Long term goals of the project are to apply these nanobodies for improved diagnostics and therapy of inflammatory diseases.