title: Role of T cell recruitment and chemokine-regulated intra-graft T cell motility patterns in corneal allograft rejection.
abstract: Keratoplasty is the primary treatment to cure blindness due to corneal opacification. However, immune-mediated rejection remains the leading cause of keratoplasty failure. Here, we utilize an in vivo imaging approach to monitor, track, and characterize in real-time the recruitment of GFP-labeled allo-specific activated (Bonzo) T cells during corneal allograft rejection. We show that the recruitment of effector T cells to the site of transplantation determined the fate of corneal allografts, and that local intra-graft production of CCL5 and CXCL9/10 regulated motility patterns of effector T cells in situ, and correlated with allograft rejection. We also show that different motility patterns associate with distinct in vivo phenotypes (round, elongated, and ruffled) of graft-infiltrating effector T cells with varying proportions during progression of rejection. The ruffled phenotype was characteristic of activated effectors T cells and predominated during ongoing rejection, which associated with significantly increased T cell dynamics within the allografts. Importantly, CCR5/CXCR3 blockade decreased the motility, size, and number of infiltrating T cells and significantly prolonged allograft survival. Our findings indicate that chemokines produced locally within corneal allografts play an important role in the in situ activation and dynamic behavior of infiltrating effector T cells, and may guide targeted interventions to promote graft survival.
authors.affiliation: Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Tan
authors.forename: M H
authors.initials: MH
authors.lastname: Abdulreda
authors.forename: F
authors.initials: F
authors.lastname: Cruz-Guilloty
authors.forename: N
authors.initials: N
authors.lastname: Cutrufello
authors.forename: A
authors.initials: A
authors.lastname: Shishido
authors.forename: R E
authors.initials: RE
authors.lastname: Martinez
authors.forename: S
authors.initials: S
authors.lastname: Duffort
authors.forename: X
authors.initials: X
authors.lastname: Xia
authors.forename: J
authors.initials: J
authors.lastname: Echegaray-Mendez
authors.forename: R B
authors.initials: RB
authors.lastname: Levy
authors.forename: P-O
authors.initials: PO
authors.lastname: Berggren
authors.forename: V L
authors.initials: VL
authors.lastname: Perez
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology*; D018925:Chemokines / Q000276:immunology* / Q000378:metabolism; D003315:Cornea / Q000276:immunology* / Q000473:pathology; D003316:Corneal Diseases / Q000601:surgery; D016039:Corneal Transplantation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival; D007111:Immunity, Cellular; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D014184:Transplantation, Homologous
chemical_list: D018925:Chemokines