title: 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.
authors.affiliation: Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Vadim A
authors.initials: VA
authors.lastname: Villarroel
authors.affiliation: Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Naoko
authors.initials: N
authors.lastname: Okiyama
authors.affiliation: Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Gaku
authors.initials: G
authors.lastname: Tsuji
authors.affiliation: Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jay T
authors.initials: JT
authors.lastname: Linton
authors.affiliation: Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. Electronic address: katzs@od.niams.nih.gov.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Katz
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002465:Cell Movement; D002469:Cell Separation; D054357:Chemokine CXCL10 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000378:metabolism; D053547:Keratin-14 / Q000378:metabolism; D008024:Ligands; D008198:Lymph Nodes / Q000166:cytology; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000378:metabolism; D011401:Promoter Regions, Genetic; D054367:Receptors, CXCR3 / Q000378:metabolism*; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology; D015854:Up-Regulation
chemical_list: D017252:CD3 Complex; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; C485433:Cxcl10 protein, mouse; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D053547:Keratin-14; D008024:Ligands; D054367:Receptors, CXCR3; D010047:Ovalbumin