CXCR3-Mediated Skin Homing of Autoreactive CD8 T Cells Is a Key Determinant in Murine Graft-Versus-Host Disease

Abstract

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.