An activating mutation in CD45 generates a novel murine model of hemophagocytic disorders in the context of a MHC Class 1 restricted TCR. (109.11)

Abstract

Hemophagocytic syndromes encompass a spectrum of life-threatening disorders characterized by severe systemic inflammation and mechanistically are not well understood. We inadvertently generated a novel mouse model that shares many characteristics of these hyperinflammatory conditions. Expression of a single activating point mutation (E613R) in the receptor protein tyrosine phosphatase CD45 results in a lupus-like phenotype on a mixed C57Bl/6 (B6)-129/Sv genetic background. However, CD45E613R mice on an inbred B6 background show no stigmata of disease despite inappropriate regulation of signals emanating from CD45’s substrates, the src family kinases. Surprisingly, introduction of a MHC class I restricted T cell receptor specific for ovalbumin (OT1) into B6 CD45E613R mice results in a severe hyperinflammatory disease reminiscent of hemophagocytic syndromes. Disease is maintained in RAG1 deficient CD45E613R/OTI mice implicating myeloid and/or CD8 T cells in disease pathogenesis. Using an adoptive transfer approach, we find CD45E613R/OT1 CD8 T cells are necessary and sufficient for this phenotype. Further analysis of CD45E613R/OT1 T cells indicates that they are inappropriately activated, secrete excessive levels of interferon gamma, and have defective cytolytic function. These intriguing results support further analysis of the role of src family kinase mediated signaling networks in hemophagocytic disorders.