SummaryMigration of activated regulatory T (Treg) cells to inflamed tissue is crucial for their immune-modulatory function. While metabolic reprogramming during Treg cell differentiation has been extensively studied, the bioenergetics of Treg cell trafficking remains undefined. We have investigated the metabolic demands of migrating Treg cells in vitro and in vivo. We show that glycolysis was instrumental for their migration and was initiated by pro-migratory stimuli via a PI3K-mTORC2-mediated pathway culminating in induction of the enzyme glucokinase (GCK). Subsequently, GCK promoted cytoskeletal rearrangements by associating with actin. Treg cells lacking this pathway were functionally suppressive but failed to migrate to skin allografts and inhibit rejection. Similarly, human carriers of a loss-of-function GCK regulatory protein gene—leading to increased GCK activity—had reduced numbers of circulating Treg cells. These cells displayed enhanced migratory activity but similar suppressive function, while conventional T cells were unaffected. Thus, GCK-dependent glycolysis regulates Treg cell migration.
Context Accelerated atherosclerosis has been described in antiphospholipid syndrome, but the vascular abnormalities and the underlying mechanisms remain unclear.Objectives To compare vascular structure and function in patients with positive antiphospholipid antibodies (aPL) with controls and to assess their relationship with paraoxonase activity.
Design, Setting, and ParticipantsA cross-sectional study of 77 women with positive antiphospholipid antibodies from a lupus outpatient clinic in London, England (90% of the eligible population) and 77 controls matched on frequency basis for age and cardiovascular risk factors between June 2006 and April 2009. Carotid intima media thickness (CIMT), flow-mediated dilatation, pulse wave velocity, and paraoxonase activity were measured in all patients. Anti-inflammatory and antioxidant properties of high-density lipoprotein (HDL) were examined.Main Outcome Measures CIMT, pulse wave velocity, flow-mediated dilatation, and paraoxonase.
ResultsWomen with aPL had greater CIMT and pulse wave velocity compared with controls (mean [SD], 0.75 [0.16] vs 0.64 [0.
SummaryEffector-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.
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