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Autoimmunity-associated protein tyrosine phosphatase PEP negatively regulates IFN-α receptor signaling.

Holmes DA, Suto E, Lee WP, Ou Q, Gong Q, Smith HR, Caplazi P, Chan AC - J. Exp. Med. (2015)

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.

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Affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.

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PEP and IFNAR are required for IFN-α–mediated progenitor proliferation. (A) Analysis of progenitor proliferation in BM chimeric mice. Pep+/+ (red) and Pep−/− (blue) chimeric mice were treated with poly(I:C) for 23 h, followed by BrdU administration for 1 h. BrdU incorporation of BM progenitors was analyzed by FACS (left). Graphical representation (right) of BrdU incorporation in myeloid progenitors from donor (CD45.2+; middle) Pep+/+ (open circle) and Pep−/− (grey square) mice or myeloid progenitors from wild-type competitor (CD45.1+) mice (right). n = 4 mice/genotype and data shown are representative of 3 independent experiments. (B) Pep−/− mice were untreated (left) and compared with Pep−/− (middle) or Pep−/−IFNAR−/− (right) chimeric mice injected with poly(I:C). Sca-1 levels were assessed by FACS 24 h after poly(I:C) administration. A representative FACS plot is depicted here and quantitated in C. (C) Graphical representation of percentage of LS−K lineage− BM from B in untreated (circle), poly(I:C)-treated Pep−/− (squares), or poly(I:C)-treated Pep−/−IFNAR−/− (triangle) mice. n = 4 mice/genotype and data shown are representative of 3 independent experiments. Values in graphs represent means ± SEM. Statistical analysis was done by two-tailed paired Student’s t test. ***, P < 0.001.
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fig4: PEP and IFNAR are required for IFN-α–mediated progenitor proliferation. (A) Analysis of progenitor proliferation in BM chimeric mice. Pep+/+ (red) and Pep−/− (blue) chimeric mice were treated with poly(I:C) for 23 h, followed by BrdU administration for 1 h. BrdU incorporation of BM progenitors was analyzed by FACS (left). Graphical representation (right) of BrdU incorporation in myeloid progenitors from donor (CD45.2+; middle) Pep+/+ (open circle) and Pep−/− (grey square) mice or myeloid progenitors from wild-type competitor (CD45.1+) mice (right). n = 4 mice/genotype and data shown are representative of 3 independent experiments. (B) Pep−/− mice were untreated (left) and compared with Pep−/− (middle) or Pep−/−IFNAR−/− (right) chimeric mice injected with poly(I:C). Sca-1 levels were assessed by FACS 24 h after poly(I:C) administration. A representative FACS plot is depicted here and quantitated in C. (C) Graphical representation of percentage of LS−K lineage− BM from B in untreated (circle), poly(I:C)-treated Pep−/− (squares), or poly(I:C)-treated Pep−/−IFNAR−/− (triangle) mice. n = 4 mice/genotype and data shown are representative of 3 independent experiments. Values in graphs represent means ± SEM. Statistical analysis was done by two-tailed paired Student’s t test. ***, P < 0.001.

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).


Autoimmunity-associated protein tyrosine phosphatase PEP negatively regulates IFN-α receptor signaling.

Holmes DA, Suto E, Lee WP, Ou Q, Gong Q, Smith HR, Caplazi P, Chan AC - J. Exp. Med. (2015)

PEP and IFNAR are required for IFN-α–mediated progenitor proliferation. (A) Analysis of progenitor proliferation in BM chimeric mice. Pep+/+ (red) and Pep−/− (blue) chimeric mice were treated with poly(I:C) for 23 h, followed by BrdU administration for 1 h. BrdU incorporation of BM progenitors was analyzed by FACS (left). Graphical representation (right) of BrdU incorporation in myeloid progenitors from donor (CD45.2+; middle) Pep+/+ (open circle) and Pep−/− (grey square) mice or myeloid progenitors from wild-type competitor (CD45.1+) mice (right). n = 4 mice/genotype and data shown are representative of 3 independent experiments. (B) Pep−/− mice were untreated (left) and compared with Pep−/− (middle) or Pep−/−IFNAR−/− (right) chimeric mice injected with poly(I:C). Sca-1 levels were assessed by FACS 24 h after poly(I:C) administration. A representative FACS plot is depicted here and quantitated in C. (C) Graphical representation of percentage of LS−K lineage− BM from B in untreated (circle), poly(I:C)-treated Pep−/− (squares), or poly(I:C)-treated Pep−/−IFNAR−/− (triangle) mice. n = 4 mice/genotype and data shown are representative of 3 independent experiments. Values in graphs represent means ± SEM. Statistical analysis was done by two-tailed paired Student’s t test. ***, P < 0.001.
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Related In: Results  -  Collection

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fig4: PEP and IFNAR are required for IFN-α–mediated progenitor proliferation. (A) Analysis of progenitor proliferation in BM chimeric mice. Pep+/+ (red) and Pep−/− (blue) chimeric mice were treated with poly(I:C) for 23 h, followed by BrdU administration for 1 h. BrdU incorporation of BM progenitors was analyzed by FACS (left). Graphical representation (right) of BrdU incorporation in myeloid progenitors from donor (CD45.2+; middle) Pep+/+ (open circle) and Pep−/− (grey square) mice or myeloid progenitors from wild-type competitor (CD45.1+) mice (right). n = 4 mice/genotype and data shown are representative of 3 independent experiments. (B) Pep−/− mice were untreated (left) and compared with Pep−/− (middle) or Pep−/−IFNAR−/− (right) chimeric mice injected with poly(I:C). Sca-1 levels were assessed by FACS 24 h after poly(I:C) administration. A representative FACS plot is depicted here and quantitated in C. (C) Graphical representation of percentage of LS−K lineage− BM from B in untreated (circle), poly(I:C)-treated Pep−/− (squares), or poly(I:C)-treated Pep−/−IFNAR−/− (triangle) mice. n = 4 mice/genotype and data shown are representative of 3 independent experiments. Values in graphs represent means ± SEM. Statistical analysis was done by two-tailed paired Student’s t test. ***, P < 0.001.
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).

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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.

Show MeSH
Related in: MedlinePlus