T Cell Homeostasis in Systemic Autoimmunity

Scripps Research Institute, The, La Jolla CA

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Abstract

DESCRIPTION (provided by the applicant): It has recently been documented that peripheral mature T cell survival and homeostasis depend on self-recognition. Contrary to previous assumptions, naive T cells require constant engagement of their antigen receptors with self-MHC/peptide ligands to persist in a quiescent state. More importantly, in a lymphopenic state, it is this self-MHC/peptide recognition that leads to T cell expansion and reestablishment of the normal lymphocyte pool size. The hypothesis to be tested herein is that induction and maintenance of systemic autoimmune disease, such as lupus, in appropriate backgrounds is the result of homeostatic T cell perturbations leading to engagement and enrichment of disease-inducing anti-self T cell clones. In support of this is the reported development of autoimmunity in rodents following lymphopenia induced by neonatal thymectomy, cyclosporin treatment, viral infection or irradiation. To address the possibility that T cell homeostasis defects contribute to lupus pathogenesis, we propose to compare the following in lupus-predisposed and normal mice: a) thymic output and peripheral T cell turnover using isotopic, staining and molecular techniques; b) homeostatic proliferation rates, activation marker acquisition, cytokine expression, cell-cycle and apoptosis characteristics using functional and molecular approaches; c) selection pressures and modifications in T cell repertoires during homeostatic expansion, including selection of high avidity self-reactive T cell clones with increased pathogenic potential, defined by cloning and adoptive transfer experiments, and 'd) the capacity of naive and activated/memory T cells of lupus mice to act as "bystander inhibitors of homeostatic proliferation, and of "regulatory" T cells to interfere with this process and prevent lupus development. These results will further define the biology of homeostatic anti-self T cell proliferation, land may provide a new paradigm for understanding autoimmune syndromes, including lupus.