CC chemokine receptor 2 expression in donor cells serves an essential role in graft-versus-host-disease

J Immunol. 2003 Nov 1;171(9):4875-85. 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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


  • Ccr2 protein, mouse
  • Chemokines
  • Cytokines
  • Receptors, CCR2
  • Receptors, Chemokine
  • Interferon-gamma