CC Chemokine Receptor 2 Expression in Donor Cells Serves an Essential Role in Graft-versus-Host-Disease

• Published in: The Journal of immunology (1950) 2003-11, Vol.171 (9), p.4875-4885
• Main Authors: Rao, Arun R, Quinones, Marlon P, Garavito, Edgar, Kalkonde, Yogeshwar, Jimenez, Fabio, Gibbons, Caroline, Perez, Jennifer, Melby, Peter, Kuziel, William, Reddick, Robert L, Ahuja, Sunil K, Ahuja, Seema S
• Format: Article
• Language: English
• Subjects: Acute Disease; Anemia, Aplastic - genetics; Anemia, Aplastic - immunology; Anemia, Aplastic - mortality; Anemia, Aplastic - pathology; Animals; Apoptosis - genetics; Apoptosis - immunology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; CD4-Positive T-Lymphocytes - transplantation; Cell Separation; Cells, Cultured; Chemokines - biosynthesis; Chronic Disease; Cytokines - biosynthesis; Down-Regulation - genetics; Down-Regulation - immunology; Graft Survival - genetics; Graft Survival - immunology; Graft vs Host Disease - genetics; Graft vs Host Disease - immunology; Graft vs Host Disease - mortality; Graft vs Host Disease - pathology; Interferon-gamma - biosynthesis; Interferon-gamma - physiology; Lymphocyte Activation - genetics; Lymphocyte Transfusion - mortality; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, CCR2; Receptors, Chemokine - biosynthesis; Receptors, Chemokine - deficiency; Receptors, Chemokine - genetics; Receptors, Chemokine - physiology; Spleen - cytology; Spleen - metabolism; Spleen - pathology; Spleen - transplantation
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.171.9.4875

The complete repertoire of cellular and molecular determinants that influence graft-vs-host disease (GVHD) is not known. Using a well-established murine model of GVHD (B6-->bm12 mice), we sought to elucidate the role of the donor non-T cell compartment and molecular determinants therein in the pathogenesis of GVHD. In this model the acute GVHD-inducing effects of purified B6 wild-type (wt) CD4(+) T cells was inhibited by wt non-T cells in a dose-dependent manner. Paradoxically, unlike the chronic GVHD phenotype observed in bm12 mice transplanted with B6wt unfractionated splenocytes, bm12 recipients of B6ccr2-null unfractionated splenocytes developed acute GVHD and died of IFN-gamma-mediated bone marrow aplasia. This switch from chronic to acute GVHD was associated with increased target organ infiltration of activated CD4(+) T cells as well as enhanced expression of Th1/Th2 cytokines, chemokines, and the antiapoptotic factor bfl1. In vitro, ccr2(-/-) CD4(+) T cells in unfractionated splenocytes underwent significantly less activation-induced cell death than B6wt CD4(+) T cells, providing another potential mechanistic basis along with enhanced expression of bfl1 for the increased numbers of activated T cells in target organs of B6ccr2(-/-) splenocyte-->bm12 mice. Collectively, these findings have important clinical implications, as they implicate the donor non-T cell compartment as a critical regulator of GVHD and suggest that ccr2 expression in this cellular compartment may be an important molecular determinant of activation-induced cell death and GVHD pathogenesis.