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: Previous studies have shown that chronic type I IFN stimulation induces hematopoietic progenitors to proliferate and lose self-renewal capacity, resulting in exhaustion and HSC dysfunction (Essers et al., 2009). To investigate the mechanism leading to decreased numbers of progenitor cells in Pep−/− BM after IFN-α treatment, we assessed BrdU incorporation by progenitor cells as a measure of progenitor proliferation. Consistent with increased activation observed in poly(I:C)-treated mice (Fig. 2 G), Pep−/− myeloid progenitors incorporated BrdU at a higher rate compared to Pep+/+ progenitors in poly(I:C)-treated mice (Fig. 3 A). We observed a similar increase in BrdU in Pep−/− compared to Pep+/+ myeloid progenitors after low-dose Ad5-IFN-α5 (107 PFU/mouse) administration (Fig. 3 B). This increased proliferation in Pep−/− LS−K, MEP, and CMP/GMP progenitors were associated with increased entry into the cell cycle after poly(I:C) treatment (Fig. 3, D–F). In contrast, no differences in BrdU incorporation or cell cycling were detected between Pep+/+ and Pep−/− HSC progenitors (LSK) after poly(I:C) treatment (Fig. 3 C).
Affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.