CCR4 expression on host T cells is a driver for alloreactive responses and lung rejection
Vyacheslav Palchevskiy, Ying Ying Xue, Rita Kern, Stephen S. Weigt, Aric L. Gregson, Sophie X. Song, Michael C. Fishbein, Cory M. Hogaboam, David M. Sayah, Joseph P. Lynch III, Michael P. Keane, David G. Brooks, John A. Belperio
Vyacheslav Palchevskiy, Ying Ying Xue, Rita Kern, Stephen S. Weigt, Aric L. Gregson, Sophie X. Song, Michael C. Fishbein, Cory M. Hogaboam, David M. Sayah, Joseph P. Lynch III, Michael P. Keane, David G. Brooks, John A. Belperio
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Research Article Immunology Transplantation

CCR4 expression on host T cells is a driver for alloreactive responses and lung rejection

Abstract

Despite current immunosuppressive strategies, long-term lung transplant outcomes remain poor due to rapid allogenic responses. Using a stringent mouse model of allo-airway transplantation, we identified the CCR4-ligand axis as a central node driving secondary lymphoid tissue homing and activation of the allogeneic T cells that prevent long-term allograft survival. CCR4 deficiency on transplant recipient T cells diminished allograft injury and when combined with CTLA4-Ig led to lung allograft accommodation lasting longer than in any previous study to our knowledge. Thus, we identify CCR4-ligand interactions as a central mechanism driving allogeneic transplant rejection and suggest it as a potential target to enhance long-term lung transplant survival.

Authors

Vyacheslav Palchevskiy, Ying Ying Xue, Rita Kern, Stephen S. Weigt, Aric L. Gregson, Sophie X. Song, Michael C. Fishbein, Cory M. Hogaboam, David M. Sayah, Joseph P. Lynch III, Michael P. Keane, David G. Brooks, John A. Belperio

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Figure 6

Hierarchy for T cells reestablishing rejection in CCR4–/– recipient mice.

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Hierarchy for T cells reestablishing rejection in CCR4–/– recipient mice...
CD8+ (5 × 106), CD4+ (5 × 106), and CD90.2+ (1 × 107) T cells from either CCR4–/– or CCR4+/+ naive mice were transferred to CCR4–/– recipients of BALB/c airway grafts on day 0, and the allografts were analyzed for rejection scores on day 21. (A and B) Rejection scores of allografts from CCR4–/– recipients (recip) with the transfer of (A) CD8+ T cells and (B) CD4+ and CD90.2 T cells. See also Supplemental Figure 5. (C) Representative H&E staining of day 21 transplanted BALB/c airways from adoptively transferred CD4+ T cells from either CCR4+/+ or CCR4–/– naive mice transferred into CCR4–/– recipients on day 0. CCR4–/– recipients with transferred CCR4–/– CD4+ T cells have a virtually normal epithelium without fibroblasts obstructing the lumen. Allografts from the CCR4–/– recipients with transferred CCR4+/+ CD4+ T cells have a denuded airway epithelium with a moderate amount of fibroblasts invading the airway lumen. In separate experiments, CCR4+/+ CD4+ T cells (5 × 106) were transferred to CCR4–/– recipients with either control Ab or the depleting anti-CD8 Ab delivered on days –1, 7, and 14, and the allografts were analyzed for rejection scores on day 21. (D) Rejection scores of allografts from CCR4–/– recipients with the transfer of CCR4+/+ CD4+ T cells with or without anti-CD8 Ab. (E) CCR4–/– recipients with transferred CCR4+/+ CD4+ T cells plus a control Ab have a loss of airway epithelium with a moderate amount of fibroblasts obstructing the lumen. CCR4–/– recipients with transferred CCR4+/+ CD4+ T cells plus an anti-CD8 Ab have a denuded airway epithelium and minimal airway invading fibroblasts. Original magnification, ×5 (left panels), ×20 (right panels). Data are representative of 10–16 mice per group. Error bars indicate SEM. Significance was determined by Mann-Whitney U test or Kruskal-Wallis with post hoc Dunn’s test where appropriate; *P < 0.05.