Host-Derived CD8+ Dendritic Cells Protect Against Acute Graft-versus-Host Disease after Experimental Allogeneic Bone Marrow Transplantation Michael Weber,

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Host-Derived CD8+ Dendritic Cells Protect Against Acute Graft-versus-Host Disease after Experimental Allogeneic Bone Marrow Transplantation Michael Weber, Berenice Rudolph, Pamela Stein, Nir Yogev, Markus Bosmann, Hansjörg Schild, Markus P. Radsak Biology of Blood and Marrow Transplantation Volume 20, Issue 11, Pages 1696-1704 (November 2014) DOI: 10.1016/j.bbmt.2014.08.005 Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Enhanced GVHD-related mortality in the absence of conventional of CD8α+ DCs. (A-C) Recipient mice (B6, CD11c-DTA, CD11c-iDTR or Batf3-/- as indicated) were lethally irradiated (11 Gy in split dose) and transplanted allogeneic T cell–depleted bone marrow cells (5 × 106 cells) and CD90.2+ T cells (5 × 105 cells) from BALB/c donor mice. Kaplan-Meier survival analysis of GVHD-related mortality of the indicated treatment groups is shown. In (B) the indicated group of CD11c-iDTR mice received diphtheria toxin (25 ng/g, on days –2 and 1) for DC depletion. The results in (A) show a single experiment. The analyses in (B, C) are cumulated from 2 independent experiments with 5 to 8 mice per group. (D) HSCT was performed as in (C) except mice were killed on day 10. Samples from the intestine, liver, and skin were taken and sections were stained with H & E and histopathological scores (inflammation, apoptosis) determined (n = 7 per group). *Statistical significance (P < .05) by Mantel-Cox test. **Statistical significance (P < .05) by Student's t-test. Biology of Blood and Marrow Transplantation 2014 20, 1696-1704DOI: (10.1016/j.bbmt.2014.08.005) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Host DCs are activated but rapidly depleted after HSCT. Recipient B6 mice were lethally irradiated (11 Gy in split dose) and transplanted allogeneic T cell–depleted bone marrow cells (5 × 106 cells) and CD90.2+ T cells (5 × 105 cells) from BALB/c donor mice as described before. Splenocytes were harvested at the indicated time points and stained for viable DCs (identified by propidium iodide− CD11c+ MHC II+ cells). (A) The absolute number of DCs was determined using calibrated counting beads. The cumulated results from 2 independent experiments are depicted (n = 6 per time point). (B) Representative flow cytometry overlay histograms of splenic DCs (gated on propidium iodide− CD11c+ MHC II+ cells) for surface expression of MHC II, CD80, and CD86, respectively, of untreated mice (red) or 24 hours after HSCT (blue) are depicted. (C) Mice were left untreated (B6 or Batf3-/-) or lethally irradiated (11 Gy in split dose) and spleens (left) and MLNs were harvested 24 hours later and analyzed by flow cytometry for CD8α+ DCs (gating on propidium iodide− CD3−CD19- F4/80- and CD11c+ MHC II+ cells). A cumulative analysis of 2 independent experiments with 6 mice per group is shown. (D) Representative flow cytometry histograms of splenic DCs (gated on propidium iodide− CD11c+ MHC II+ cells) and shown after staining for the donor (BALB) specific marker CD229.1 at the indicated time points post HSCT. The percentage of donor-derived DCs is indicated. *Significant difference (P < .05) to the untreated control group by 1-way ANOVA and Bonferroni's posttest comparison. **Significant difference (P < .05) between the indicated groups by Student's t-test. Biology of Blood and Marrow Transplantation 2014 20, 1696-1704DOI: (10.1016/j.bbmt.2014.08.005) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Enhanced activation of conventional DCs in the absence of CD8α+ DCs after TBI. Mice were left untreated (B6 or Batf3-/-) or lethally irradiated (11 Gy in split dose as before; B6 post TBI or Batf3-/- post TBI) and MLNs were harvested 24 hours after TBI. (A) The cells were stained for viable DCs (identified by propidium iodide− CD11c+ MHC II+ cells, indicated as “all”). DCs from B6 mice were further subdivided by the surface expression of CD8α (indicated as CD8+ or CD8−) and analyzed by flow cytometry. The expression levels MHC II and the activation markers CD80/CD86 are quantified in the respective DC subsets. The expression levels of the inhibitory B7 family molecules PD-L1 and PD-L2 were quantified on DCs (gating on propidium iodide− CD11c+ MHC II+ cells). The depicted data are mean and SD from 1 representative of 3 independent experiments performed with 3 mice per group. (B) Total RNA was extracted from MLN cells of untreated mice or 24 hours post-TBI (B6 or Batf3-/-). mRNA levels of Il12p35, Il10 and Ifng (mean plus SD) were assessed by real-time PCR and normalized to levels of untreated mice. B2m was used as housekeeping gene. Data shown are from 1 representative (n = 3 mice per group) of 2 independent experiments. *Significant difference (P < .05) between the indicated groups by 1-way ANOVA and Bonferroni's post-test comparison. **Statistical significance (P < .05) by Student's t-test. #Statistical significance (P < .05) by Student's t-test compared with the untreated control (B6 or Batf3-/-). Biology of Blood and Marrow Transplantation 2014 20, 1696-1704DOI: (10.1016/j.bbmt.2014.08.005) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Enhanced allogeneic MLR response in the absence of CD8α+ DCs after TBI. B6 (filled bars) or Batf3-/- (open bars) mice were left untreated (A) or lethally irradiated (11 Gy in split dose as before; B6 post TBI or Batf3-/- post-TBI) (B). After 16 hours, the MLNs were isolated and used as stimulators for freshly isolated allogeneic CD90.2+ T cells from BALB/c donors at the indicated ratios. T cell proliferation was quantified after pulsing with 3H-thymidine on day 3 and harvested 18 hours later. The depicted results are mean + SD from 1 of 2 representative experiments each assayed in triplicate wells with 3 mice per group. *Ssignificant difference (P < .05) by paired Student's t-test. Biology of Blood and Marrow Transplantation 2014 20, 1696-1704DOI: (10.1016/j.bbmt.2014.08.005) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Splenic Treg cells and serum levels of TGF-β are decreased in the absence of CD8α+ DCs after HSCT. Recipient mice (B6 or Batf3-/-) were lethally irradiated (11 Gy in split dose) and transplanted allogeneic T cell–depleted bone marrow cells (5 × 106 cells) and CD90.2+ T cells (5 × 105 cells) from BALB/c donor mice as described before. (A) Splenocytes were harvested at day 7 post-HSCT and stained for viable donor-derived H2-Kb CD90.2 T cells, CD4/CD8 ratio (CD90.2+CD4+/CD90.2+CD4- cells), and Treg cells (identified by propidium iodide− CD3+ CD4+ FoxP3+ cells), respectively. The absolute number of T cells and Treg cells (mean and SD) was determined using calibrated counting beads. (B) Serum samples were collected and analyzed for IL-2 and TGF-β concentrations (mean + SD) by ELISA. The depicted results are pooled from 2 independent experiments (n = 6 per group). *Statistical significance (P < .05) by Student's t-test. n. s. indicates no significant difference by Student's t-test (P > .05). Biology of Blood and Marrow Transplantation 2014 20, 1696-1704DOI: (10.1016/j.bbmt.2014.08.005) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions