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 4

CCR4 expression is involved in naive T cell homing and intranodal activation.

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CCR4 expression is involved in naive T cell homing and intranodal activa...
CD90.2 (1 × 107) T cells from either CCR4–/– or CCR4+/+ naive mice were transferred to either CCR4–/– or CCR4+/+ recipients on day 0, and the allografts were analyzed for rejection scores on day 21. (A) Rejection scores. (B) Representative H&E staining showing that the transfer of CCR4+/+ T cells to CCR4–/– recipients leads to severe rejection, with a denuded epithelium and fibro-obliteration. However, the transfer of CCR4–/– T cells to CCR4–/– recipients causes no significant epithelial injury or fibro-obliteration. Original magnification, ×5. AT, adoptive transfer. In separate experiments, CFSE-labeled T cells from CCR4+/+ (4.0 μM, 5 × 106) and CCR4–/– (0.25 μM, 5 × 106) naive mice were transferred at a 1:1 ratio into day 7 CCR4+/+ and CCR4–/– allograft or isograft (C57BL/6 airways to C57BL/6 recipients) recipients, and 18 hours later the draining nodes were analyzed for the frequency of labeled T cells as well as their activation based on CD62L shedding using flow cytometry. (C–E) Frequency of labeled CCR4–/– and CCR4+/+ CD3+, CD4+, and CD8+ T cells. See also Supplemental Figure 3. (F) Frequency of labeled CD4+ and CD8+ T cells from CCR4–/– and CCR4+/+ naive mice that entered the lymph nodes and lost CD62L expression. See also Supplemental Figure 3. (G) Day 7 CCR4–/– and CCR4+/+ allograft recipients’ draining lymph node cells (1 × 106) were challenged with (2 × 106) irradiated BALB/c splenocytes and 16 hours later analyzed for alloresponsive CD4+ and CD8+ T cells via IFN-γ secretion. See also Supplemental Figure 4. (H) Day 7 CCR4–/– and CCR4+/+ allograft recipients were challenged with (7.5 × 106) irradiated BALB/c splenocytes with an intradermal injection into the pinna and analyzed for DTH response at 48 hours. Data are representative of 3–12 mice per group. Error bars indicate SEM. Significance was determined by Mann-Whitney U test, unpaired t test, or Kruskal-Wallis with post hoc Dunn’s test where appropriate; *P < 0.05.