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 3

CCR4–/– recipients of airway allografts attenuate rejection and have a reduction of T cells in their draining lymph nodes.

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CCR4–/– recipients of airway allografts attenuate rejection and have a r...
As described for Figure 2, BALB/c airways subcutaneously transplanted into CCR4–/– and CCR4+/+ recipients, and their whole draining lymph nodes were analyzed for T cell subpopulations via flow cytometry. (A–F) Total number and frequency of CD4+ and CD8+ T cells and their naive (Tn) and central memory (CM) T cell subpopulations from CCR4+/+ and CCR4–/– allograft recipient lymph nodes on day 7. See also Supplemental Figure 2. (G) Lymph node expression of Foxp3 by qPCR for naive nontransplanted CCR4+/+ and CCR4–/– mouse nodes as well as (H) CCR4+/+ and CCR4–/– allograft recipient nodes on day 7. Data are representative of 4–15 mice per group. Error bars indicate SEM. Significance was determined by Mann-Whitney U or unpaired t test where appropriate; *P < 0.05.