CCR2 is required for CD8-induced graft-versus-host disease

Theis H. Terwey, Theo D. Kim, Adam A. Kochman, Vanessa M. Hubbard, Sydney Lu, Johannes L. Zakrzewski, Teresa Ramirez-Montagut, Jeffrey M. Eng, Stephanie J. Muriglan, Glenn Heller, George F. Murphy, Chen Liu, Tulin Budak-Alpdogan, Onder Alpdogan, Marcel R.M. Van Den Brink

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Migration of donor-derived T cells into GVHD target organs plays a critical role in the development of GVHD and chemokines and their receptors are important molecules involved in this process. Here, we demonstrate in murine bone marrow transplantation models that the expression of the inflammatory CC chemokine receptor 2 (CCR2) on donor-derived CD8+ T cells is relevant for the control of CD8 + T-cell migration and development of GVHD. Recipients of CCR2-deficient (CCR2-/-) CD8+ T cells developed less damage of gut and liver than recipients of wild-type CD8+ T cells, which correlated with a reduction in overall GVHD morbidity and mortality. Assessment of donor CD8+ T-cell target organ infiltration revealed that CCR2-/- CD8+ T cells have an intrinsic migratory defect to the gut and liver. Other causes for the reduction in GVHD could be excluded, as alloreactive proliferation, activation, IFN-γ production and cytotoxicity of CCR2-/- CD8+ T cells were intact. Interestingly, the graft-versustumor effect mediated by CCR2-/- CD8+ T cells was preserved, which suggests that interference with T-cell migration by blockade of CCR2 signaling can separate GVHD from GVT activity.

Original languageEnglish (US)
Pages (from-to)3322-3330
Number of pages9
JournalBlood
Volume106
Issue number9
DOIs
StatePublished - Nov 2005
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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