The cooperative activity of protein tyrosine kinases and phosphatases plays a central role in regulation of T cell receptor (TCR) signal strength. Perturbing this balance, and thus the threshold for TCR signals, has profound impacts on T cell development and function. We previously generated mice containing a point mutation in the juxtamembrane wedge of the receptor-like protein tyrosine phosphatase CD45. Demonstrating the critical negative regulatory function of the wedge, the CD45 E613R (WEDGE) mutation led to a lymphoproliferative disorder (LPD) and a lupus-like autoimmune syndrome. Using genetic, cellular, and biochemical approaches, we now demonstrate that the CD45 wedge influences T cell development and function. Consistent with increased TCR signal strength, WEDGE mice have augmented positive selection and enhanced sensitivity to the CD4-mediated disease experimental autoimmune encephalitis (EAE). These correspond with hyperresponsive calcium and pERK responses to TCR stimulation in thymocytes, but surprisingly, not in peripheral T cells, where these responses are actually depressed. Together, the data support a role for the CD45 wedge in regulation of T cell responses in vivo and suggest that its effects depend on cellular context. autoimmunity ͉ tyrosine phosphatase ͉ tyrosine kinase ͉ thymocyte development T cell receptor (TCR) signal strength is influenced by the integration of multiple inputs including affinity for antigen, presence and activity of costimulatory molecules, and duration of the interaction with antigen-presenting cells (APCs) (1). Alterations in TCR signal strength impact many aspects of T cell biology including CD4 versus CD8 lineage commitment (1), effector and memory cell generation (2), and autoimmunity (3, 4). Currently, the factors defining signal strength and its functional outcome are incompletely understood.CD45, a receptor-like protein tyrosine phosphatase (RPTP) expressed on all nucleated hematopoietic cells, plays a critical positive regulatory role in antigen receptor signaling. Its absence in both mice and humans results in severe combined immunodeficiency (5, 6). CD45 mediates its effects, at least in part, by modulating the activation state of Src family protein tyrosine kinases (SFKs) (5, 7). Phosphorylation of the SFK C-terminal tyrosine by Csk inhibits the kinase while autophosphorylation of the catalytic domain tyrosine results in full activity. CD45 opposes Csk by dephosphorylating the negative regulatory tyrosine, generating a pool of primed SFKs capable of rapid activation upon receptor stimulation. In some cell types, CD45 can also dephosphorylate the catalytic tyrosine and negatively regulate SFKs.Regulation of CD45 itself is complex. Alternative splicing of the extracellular domain, regulated in a cell-and activation-specific manner, generates multiple isoforms differing in size and charge (5). Interestingly, CD45 polymorphisms influencing its alternative splicing, and thus isoform expression, are associated with several human autoimmune diseases (8). We initi...
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.
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