Hepatocyte Growth Factor Receptor c-Met Instructs T Cell Cardiotropism and Promotes T Cell Migration to the Heart via Autocrine Chemokine Release

摘要

class="head no_bottom_margin" id="sec1title">IntroductionThe migratory patterns of naive and memory T lymphocytes are well defined and vary depending on their activation, differentiation, and function. Through expression of a unique set of adhesion molecules and chemokine receptors, so-called “homing” receptors, distinct memory T cell populations are able to interact with organ-specific endothelial cells (ECs) and are recruited to distinct target tissues. For example, lymphocyte trafficking to the intestinal lamina propria is mediated by the interaction between intestinal mucosal addressin cell adhesion molecule-1 expressed by gut endothelium, and lymphocyte α4β7 integrin. T cell migration to the skin is promoted by cutaneous lymphocyte-associated antigen (CLA) interaction with vascular E-selectin with the involvement of chemokine-receptor pairs CCR4-CCL17, CCR10-CCL27, and CCR8-CCL1 ().During antigen activation of naive T cells, the microenvironment of the draining lymphoid tissue provides vital cues for the acquisition of peripheral homing preference. For example, dendritic cells (DCs) derived from gut-associated lymphoid tissue (GALT) have been shown to instruct gut tropism, via the production of retinoic acid from vitamin A (). Similarly, skin DCs produce the vitamin D3 metabolite 1,25(OH)2D3, which favors the induction of skin-homing lymphocytes (). With the exception of gut and skin, the molecular signature and imprinting mechanisms that define preferential homing to other organs are largely elusive. Most studies have focused on the role of adhesion and chemokine receptors, but the extensive overlap in the expression of these molecules by lymphocytes retrieved from different tissues has prevented the identification of tissue-selective area codes.It has been recently proposed that soluble factors produced by the tissue itself might contribute to T cell homing imprinting. For example, skin-derived soluble factors have been shown to induce the skin homing receptor CCR8 in T cells (). It is known that tissue-derived small molecules can be directly delivered to draining lymph nodes by anatomically defined conduits (). Some of these molecules are produced in a tissue-specific manner and can therefore define the topographic identity of the tissue where they are generated in the draining lymphoid tissue and possibly contribute to T cell homing imprinting ().HGF is a pleiotropic cytokine that plays important functions in organ development, regeneration, and cancer by activating its tyrosine kinase receptor c-Met (). A key feature of HGF is its ability to promote cell migration (). In immune processes, HGF can induce chemotactic responses by liver-derived human T lymphocytes () and maintains the differentiation of human hepatic sinusoidal endothelial cells, which specialize in lymphocyte recruitment to the liver (). The HGF-c-Met axis has also been implicated in the mobilization of cardiac progenitor cells (). Based on these reports, we have investigated the effects of T cell exposure to HGF during activation on their migration and homing patterns. Our findings reveal that engagement of HGF-c-Met axis during priming induces “heart-homing” signature T cells and also indirectly mediates their recirculation in cardiac tissue.