Hepatocyte Growth Factor Receptor c-Met Instructs T Cell Cardiotropism and Promotes T Cell Migration to the Heart via Autocrine Chemokine Release.
1087 - 1099
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Effector-T-cell-mediated immunity depends on the efficient localization of antigen-primed lymphocytes to antigen-rich non-lymphoid tissue, which is facilitated by the expression of a unique set of "homing" receptors acquired by memory T cells. We report that engagement of the hepatocyte growth factor (HGF) receptor c-Met by heart-produced HGF during priming in the lymph nodes instructs T cell cardiotropism, which was associated with a specialized homing "signature" (c-Met(+)CCR4(+)CXCR3(+)). c-Met signals facilitated T cell recruitment to the heart via the chemokine receptor CCR5 by inducing autocrine CCR5 ligand release. c-Met triggering was sufficient to support cardiotropic T cell recirculation, while CCR4 and CXCR3 sustained recruitment during heart inflammation. Transient pharmacological blockade of c-Met during T cell priming led to enhanced survival of heart, but not skin, allografts associated with impaired localization of alloreactive T cells to heart grafts. These findings suggest c-Met as a target for development of organ-selective immunosuppressive therapies.
AuthorsKomarowska, I; Coe, D; Wang, G; Haas, R; Mauro, C; Kishore, M; Cooper, D; Nadkarni, S; Fu, H; Steinbruchel, DA; Pitzalis, C; Anderson, G; Bucy, P; Lombardi, G; Breckenridge, R; Marelli-Berg, FM
- Cardiovascular