Autoimmunity-associated protein tyrosine phosphatase PEP negatively regulates IFN-α receptor signaling.
Bottom Line: Pep(-/-) hematopoietic progenitors demonstrate increased IFNAR signaling, increased IFN-inducible gene expression, and enhanced proliferation and activation compared to Pep(+/+) progenitors in response to IFN-α.In addition, Pep(-/-) mice treated with IFN-α display a profound defect in hematopoiesis, resulting in anemia, thrombocytopenia, and neutropenia when compared to IFN-α-treated Pep(+/+) mice.As SLE patients carrying the PTPN22(C1858T) risk variant have higher serum IFN-α activity, these data provide a molecular basis for how type I IFNs and PTPN22 may cooperate to contribute to lupus-associated cytopenias.
Affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.Show MeSH
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Mentions: To determine the hematopoietic requirement for PEP in IFN-α–mediated hematopoietic progenitor proliferation, we generated mixed BM chimeras by transferring Pep+/+ or Pep−/− donor (CD45.2+) BM competitively with host (CD45.1+) BM at a 1:1 ratio. Reconstituted chimeric mice were treated with poly(I:C) and administered BrdU 24 h later. Donor-derived CD45.2+Pep−/− myeloid progenitors (LS−K) incorporated more BrdU compared to donor-derived CD45.2+Pep+/+ myeloid progenitors (Fig. 4 A, left graph). In contrast, host-derived (CD45.1+) myeloid progenitors (LS−K) incorporated BrdU equivalently (Fig. 4 A, right graph).
Affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.