Effects of purine nucleoside phosphorylase deficiency on thymocyte development Taniya Papinazath, MSc, Wexian Min, MSc, Suntharalingam Sujiththa, BSc,

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Presentation transcript:

Effects of purine nucleoside phosphorylase deficiency on thymocyte development Taniya Papinazath, MSc, Wexian Min, MSc, Suntharalingam Sujiththa, BSc, Amos Cohen, PhD, Cameron Ackerley, PhD, Chaim M. Roifman, MD, Eyal Grunebaum, MD Journal of Allergy and Clinical Immunology Volume 128, Issue 4, Pages 854-863.e1 (October 2011) DOI: 10.1016/j.jaci.2011.07.039 Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Effects of PNP deficiency on thymocytes. A, In the absence of PNP, dGuo can only be phosphorylated by the mitochondrial dGK to dGMP and subsequently to dGTP. Excess dGTP might impair mitochondrial DNA maintenance and disrupt the mitochondria, leading to cytochrome c release into the cytosol and apoptosis. B, Representative contour plots depicting the percentages of CD4-expressing thymocytes, CD8-expressing thymocytes, or both. Pooled data from 15 mice of each genotype are summarized in the bar graph (means ± SDs). C, Representative contour plots depicting the percentages of CD4-expressing thymocyte-like cells, CD8-expressing thymocyte-like cells, or both after 21 days of ex vivo differentiation on OP9-DL1 cells. Pooled data from 4 independent experiments are summarized in the bar graph (means ± SDs). Journal of Allergy and Clinical Immunology 2011 128, 854-863.e1DOI: (10.1016/j.jaci.2011.07.039) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 PNP deficiency causes increased apoptosis of DP thymocytes. A, Contour plots depicting the percentages of cells excluding PI and expressing Annexin V among DP thymocytes, as determined by means of FACS analysis. Results are representative of 10 mice per genotype in 4 independent experiments. B, Transmission electron microscopic view demonstrating cells at various apoptotic stages in the corticomedullary junction of the thymus of a PNP-KO mouse. These include compaction of nuclear chromatin into a sharply circumscribed uniform electron-dense structure (left), margination of the nuclear chromatin into the cell’s periphery (middle), and chromatin breakups into discrete fragments (right). Results are representative of 3 mice from 2 independent experiments. Journal of Allergy and Clinical Immunology 2011 128, 854-863.e1DOI: (10.1016/j.jaci.2011.07.039) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 dGuo induces apoptosis of PNP-deficient DP thymocytes. A, Contour plots depicting the percentages of cells excluding PI and expressing Annexin V after overnight culture of DP thymocytes without (−) or with (+) 12.5 μmol/L dGuo. B, Bar graph depicting the percentages (means ± SDs) of PI-excluding and Annexin V– expressing DP, as well as CD4+ and CD8+ SP, thymocytes after overnight culture with increasing dGuo concentrations. UT, Without dGuo. ∗P = .008 and ∗∗P < .001 between DP thymocytes from normal and PNP-KO mice. C, Histograms depicting the percentages of DP thymocytes not accumulating CMXRos (having disrupted MMP) after overnight culture with 12.5 μmol/L dGuo. D, Bar graph depicting the percentages (means ± SDs) of DP thymocytes from PNP-KO mice excluding PI and expressing Annexin V after overnight culture without (UT) or with 12.5 μmol/L dGuo. TAT-PNP (10 U/mL) was added to some of the cultures. All FACS analyses are representative of at least 4 independent experiments. Journal of Allergy and Clinical Immunology 2011 128, 854-863.e1DOI: (10.1016/j.jaci.2011.07.039) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 dGuo induces apoptosis in the mitochondria of PNP-deficient thymocytes. A, Bar graph depicting the percentages (means ± SDs) of DP thymocytes that have fragmented DNA (terminal deoxynucleotidyl transferase–mediated UTP nick end labeling positive) or disrupted MMP and hence not accumulating MitoTracker Red CMXRos after overnight treatment with 12.5 μmol/L dGuo, as determined by means of FACS analysis. Results represent pooled data from 4 independent experiments. B, Western blotting of cytochrome c (CytoC) in the mitochondria (M) and cytosol (C) of DP thymocytes from PNP-KO mice after treatment with 12.5 μmol/L dGuo or dexamethasone (Dex) for the indicated periods. Equal loading is determined with antibodies to the mitochondrial VDAC (Santa Cruz Biotechnology) and to the cytosolic ADA. Protein molecular weight markers (MWM) are provided. Results are representative of 3 independent experiments. C, Histograms depicting the percentages of DP thymocytes from PNP-KO mice with MMP loss (not accumulating CMXRos) and nuclear DNA fragmentation after 30 minutes of caspase inhibition with zVADfmk, followed by 24 hours of 12.5 μmol/L dGuo treatment. Results, as determined by mans of FACS analysis, are representative of 4 independent experiments. D, Contour plots depicting the percentages of Annexin V–positive cells among PI-excluding DP thymocytes from normal littermates and PNP-KO mice after overnight Fas ligation, as determined by means of FACS analysis. Results are representative of 4 independent experiments. Journal of Allergy and Clinical Immunology 2011 128, 854-863.e1DOI: (10.1016/j.jaci.2011.07.039) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 PNP deficiency does not affect the proliferation or TCR diversity of thymocytes. A, Contour plots depicting the percentages of CD4-expressing thymocytes, CD8-expressing thymocytes, or both among BrDU+ cells at the indicated days after BrDU injection. Results, as determined by means of FACS analysis, are representative of 3 independent experiments with 3 animals of each genotype per experiment. B, Bar graph depicting the percentages of DP, CD4+, and CD8+ SP thymocytes among BrDU+ cells, as determined by means of FACS analysis, 5 days after BrDU “pulse.” Results (means ± SDs) are pooled data from 3 independent experiments with analysis of 3 animals of each genotype per experiment. C, Histograms depicting the percentages of thymocyte-like cells after 21 days of ex vivo differentiation on OP9-DL1 cells that are incorporating BrDU 2 days after BrDU pulse. Results are representative of 3 independent experiments with 3 animals of each genotype per experiment. D, Bar graph depicting the percentages (means ± SDs) of CD3+ thymocytes expressing different Vβ chain families, as determined by means of FACS analysis, from 5 independent experiments. Journal of Allergy and Clinical Immunology 2011 128, 854-863.e1DOI: (10.1016/j.jaci.2011.07.039) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions