Phosphatases in Systemic Autoimmunity

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Abstract ! Systemic lupus erythematosus (SLE) presents profound T cell effector dysfunction. Interleukin-2 (IL-2) deficiency accounts for the increased infection-related morbidity and mortality rates, the defective regulatory cell (Treg) function and compromised ability to eliminate autoreactive T cells. In parallel, T cells produce increased amounts of interleukin-17 (IL-17) which is involved in tissue inflammation and damage. Protein phosphatase 2A (PP2A) is the first serine/threonine phosphatase recognized to contribute first to human SLE and later to murine lupus immunopathology. It is a trimolecular enzyme consisting of scaffolding, catalytic and regulatory subunits. We have shown that PP2Ac expression is increased in patients with SLE and that it is central to a number of signaling pathways including the suppression of the production of IL-2 and the enhancement of the production of IL-17 and that the regulatory subunit Bβ regulates IL- 2 deprivation-induced T cell death and is decreased in SLE patients. A mouse lacking PP2A in Tregs develops severe inflammation and autoimmunity because PP2Ac is needed for the suppression of the mTORC1 pathway. Using novel mice and molecular tools the proposed work will test the hypothesis that PP2Ac represents a main contributor in the immunopathogenesis of SLE and autoimmunity in general by 1) determining the importance of PP2A expression in Tregs in the regulation of the autoimmune response and related pathology; 2) determining the importance of PP2A expression in conventional T cells in the regulation of the autoimmune response and related pathology; and 3) establishing the aberrant expression of the regulatory subunit Bα in human SLE and determine how it contributes to IL-17 production. This project will generate novel concepts (differential regulation of central immune functions by PP2A, regulation of distinct functions by specific regulatory subunits) and new informative mice (mice lacking PP2A in T cell subsets and mice lacking regulatory subunits in T cells). Understanding the molecular complexity which underlies the expression of systemic autoimmunity is significant to the extent we wish to correct important pathways to treat patients. The ability to carry out parallel studies in mice and humans increases significantly the translational value of our work. ! ! !