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Direct CD137 costimulation of CD8 T cells promotes retention and innate-like function within nascent atherogenic foci.

08:00 EDT 12th April 2019 | BioPortfolio

Summary of "Direct CD137 costimulation of CD8 T cells promotes retention and innate-like function within nascent atherogenic foci."

Effector CD8 T cells infiltrate atherosclerotic lesions and are correlated with cardiovascular events, but the mechanisms regulating their recruitment and retention are not well-understood. CD137 (4-1BB) is a costimulatory receptor induced on immune cells and expressed at sites of human atherosclerotic plaque. Genetic variants associated with decreased CD137 expression correlate with carotid-intimal thickness and its deficiency in animal models attenuates atherosclerosis. These effects have been attributed in part to endothelial responses to low and disturbed flow (LDF), but CD137 also generates robust effector CD8 T cells as a costimulatory signal. Thus, we asked whether CD8 T cell-specific CD137 stimulation contributes to their infiltration, retention, and IFNγ-production in early atherogenesis. We tested this through adoptive transfer of CD8 T cells into recipient C57BL/6J mice that were then antigen-primed and CD137-costimulated. We analyzed atherogenic LDF-vessels in normolipidemic and PCSK9-mediated hyperlipidemic models and utilized a digestion protocol that allowed for lesional T cell characterization via flow cytometry and in vitro stimulation. We found that CD137 activation, specifically of effector CD8 T cells, triggers their intimal infiltration into LDF-vessels and promotes a persistent innate-like pro-inflammatory program. Residence of CD137 effector CD8 T cells further promoted infiltration of endogenous CD8 T cells with IFNγ-producing potential, while CD137-deficient CD8 T cells exhibited impaired vessel infiltration, minimal IFNγ-production, and reduced infiltration of endogenous CD8 T cells. Our studies thus provide novel insight into how CD137 costimulation of effector T cells, independent of plaque-antigen recognition, instigates their retention and promotes innate-like responses from immune infiltrates within atherogenic foci.

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This article was published in the following journal.

Name: American journal of physiology. Heart and circulatory physiology
ISSN: 1522-1539
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