CXCR3-mediated skin homing of autoreactive CD8 T cells is a key determinant in murine graft-versus-host disease

J Invest Dermatol. 2014 Jun;134(6):1552-1560. doi: 10.1038/jid.2014.2. Epub 2014 Jan 3.


The pathomechanisms underlying the development of cutaneous graft-versus-host disease (GVHD) are incompletely defined. We previously reported that K14-mOVA mice expressing membrane ovalbumin (mOVA), driven by the keratin 14 (K14) promoter, developed GVHD-like mucocutaneous disease and weight loss following transfer of OVA-specific, CD8(+) OT-I T cells. In this study, we demonstrate that early in the course of disease, the kinetics of epidermal expression of C-X-C motif chemokine ligand 9 (CXCL9) and CXCL10, interferon-γ-inducible chemokines that bind the C-X-C motif chemokine receptor 3 (CXCR3) receptor, coincides with CXCR3 expression by OT-I cells in secondary lymphoid organs. Recruitment of OT-I cells into the skin began by day 5 with progressive accumulation through day 13 post transfer. Transfer of CXCR3-knockout (CXCR3KO) OT-I cells into K14-mOVA mice resulted in strikingly attenuated skin disease. CXCR3KO OT-I cells retained full activation and effector function, but preferentially accumulated in the spleen, in contrast to wild-type (WT) OT-I cells that accumulated in skin-draining lymph nodes. Moreover, OT-I cells accounted for a significantly reduced percentage of skin-infiltrating lymphocytes in mice receiving CXCR3KO OT-I cells compared with WT OT-I cells. These results identify CXCR3 as being critical to the skin-selective effector T-cell recruitment underlying autoreactive GVHD, suggesting CXCR3 as a potential target in the treatment of GVHD and related skin diseases.

MeSH terms

  • Animals
  • CD3 Complex / metabolism
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Movement
  • Cell Separation
  • Chemokine CXCL10 / metabolism
  • Chemokine CXCL9 / metabolism
  • Epidermis / metabolism
  • Flow Cytometry
  • Graft vs Host Disease / metabolism
  • Keratin-14 / metabolism
  • Ligands
  • Lymph Nodes / cytology
  • Lymphocytes / cytology
  • Mice
  • Mice, Knockout
  • Ovalbumin / metabolism
  • Promoter Regions, Genetic
  • Receptors, CXCR3 / metabolism*
  • Skin / metabolism*
  • Skin / pathology
  • T-Lymphocytes / cytology
  • Up-Regulation


  • CD3 Complex
  • Chemokine CXCL10
  • Chemokine CXCL9
  • Cxcl10 protein, mouse
  • Cxcl9 protein, mouse
  • Cxcr3 protein, mouse
  • Keratin-14
  • Ligands
  • Receptors, CXCR3
  • Ovalbumin