Lisa A. Palmer, George E. Sale, John I

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Volume 78, Issue 1, Pages (July 2010)

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Chemokine Receptor CCR5 Mediates AlloImmune Responses in Graft-versus-Host Disease Lisa A. Palmer, George E. Sale, John I. Balogun, Dan Li, Dan Jones, Jeffrey J. Molldrem, Rainer F. Storb, Qing Ma Biology of Blood and Marrow Transplantation Volume 16, Issue 3, Pages 311-319 (March 2010) DOI: 10.1016/j.bbmt.2009.12.002 Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Infiltrating T cell lymphocytes in human aGVHD tissues are predominantly CCR5+. (A) Skin and lip biopsies of GVHD patients. Three adjacent sections of skin (top panel) and lip (lower panel) biopsies of a representative GVHD patient were stained with H&E, CCR5 antibody, or CD3 antibody. CCR5+ and CD3+ lymphocyte infiltrates were found in both the dermal and epidermal layers. (B) Lip biopsy of a representative GVHD patient with damaged salivary gland. Right and left panels are adjacent sections stained with CCR5 or CD3 antibodies. In each panel, the right side is an enlarged picture of the area with the arrow. CCR5+ and CD3+ lymphocyte infiltrates were found in the damaged area of salivary gland. Biology of Blood and Marrow Transplantation 2010 16, 311-319DOI: (10.1016/j.bbmt.2009.12.002) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Infiltrating CCR5+ T cell lymphocytes in the skin of aGVHD are both CD4+ and CD8+ T cells. The skin biopsies of a representative GVHD patient were double stained with CCR5 antibody and either CD4 antibody (top panel) or CD8 antibody (bottom panel). On the right side, CCR5+ cells are brown, and both CD4+ and CD8+ cells are Texas-Red. The same slides were photographed by light (right panel) and fluorescence microscopy (left panel) for Texas-Red. Biology of Blood and Marrow Transplantation 2010 16, 311-319DOI: (10.1016/j.bbmt.2009.12.002) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Strong CCR5 expression on T cells but not dendritic cells in aGVHD tissues. Immunohistochemistry was performed on paraffin sections for CCR5 (left panel) and Langerhans DC marker CD1a (right panel). Top panel: skin biopsy with CCR5+ T cells in the superficial dermis (arrows) and epidermis in addition to CD1a+ Langerhans DCs at sites of lymphocytic infiltration. Middle panel: foci of epidermal damage with high-level CCR5 expression in T cells (arrow) but weak CCR5 staining in CD1a+ Langerhans DCs. Bottom panel: lip biopsy from a case with minimal epithelial damage and no detectable CCR5 expression in CD1a+ Langerhans DCs. Biology of Blood and Marrow Transplantation 2010 16, 311-319DOI: (10.1016/j.bbmt.2009.12.002) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 CCR5 is coexpressed with T cell activation markers. Mixed lymphocyte culture (MLR) were used to activate PBMC from normal donors with allogenic DCs mixed with responder PBMCs (DC-MLR) at a DC:PBMC ratio of 1:100. The cells were collected 7 days after stimulation and stained with antibodies CD4, CD8, CCR5, and a panel of activation markers including CD45RA, CD45RO, CD62L, and CD69. The representative dot plots of CD4 (upper panel) and CD8 (lower panel) T cells demonstrated the coexpression of CCR5 and activation marks. Data were representative of experiments from 3 independent samples. Cells were collected on a FACscaliber Flow Cytometer and data was analyzed by Cell Quest software (Becton Dickinson). Biology of Blood and Marrow Transplantation 2010 16, 311-319DOI: (10.1016/j.bbmt.2009.12.002) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 CCR5 is upregulated on proliferating T cell lymphocytes following allogeneic activation. Responder PBMCs were incubated in CFSE for 10 minutes and then washed with PBS for coculture with allogenic DCs. Cells were collected 9 days after stimulation and stained with CD4 and CD8 antibodies. The gated lymphoblast population of CD4+ or CD8+ T cells were analyzed separately for CCR5, CCR7, and CXCR3 expression. Data shown here are representative of 3 independent samples. Biology of Blood and Marrow Transplantation 2010 16, 311-319DOI: (10.1016/j.bbmt.2009.12.002) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 6 CCR5+ T lymphocytes and intracellular cytokine production of TNFα, IL-2, and IFN-γ. Allogenic DCs mixed with responder PBMCs (DC-MLR) at a DC:PBMC ratio of 1:100. The MLR cultures were treated with brefeldin-A on day 7 for 5 hours. The cells were harvested and stained with CD4, CD8, CCR5, and intracellular cytokines TNFα (top panel), IL-2 (middle panel), and IFN-γ (bottom panel). The left panel of A (CD4) and B (CD8) were the representative dot-plots of intracellular cytokine production and the gated cells were positive for the cytokine using autologous MLR sample as the reference. The right panel of A and B was the CCR5 expression of the gated cells from the respective upper panel, and the quadrant gates were decided based on isotype control. Results were representative of 4 independent samples. Biology of Blood and Marrow Transplantation 2010 16, 311-319DOI: (10.1016/j.bbmt.2009.12.002) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions