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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.
This article was published in the following journal.
Name: American journal of physiology. Heart and circulatory physiology
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A member of the S100 PROTEIN FAMILY that regulates INFLAMMATION and the immune response. It recruits LEUKOCYTES, promotes cytokine and chemokine production, and regulates leukocyte adhesion and migration. S100A12 can also function via binding to ADVANCED GLYCOSYLATION END PRODUCT-SPECIFIC RECEPTORS, to stimulate innate immune cells.
A member of the tumor necrosis factor receptor superfamily that is specific for 4-1BB LIGAND. It is found in a variety of immune cell types including activated T-LYMPHOCYTES; NATURAL KILLER CELLS; and DENDRITIC CELLS. Activation of the receptor on T-LYMPHOCYTES plays a role in their expansion, production of cytokines and survival. Signaling by the activated receptor occurs through its association with TNF RECEPTOR-ASSOCIATED FACTORS.
A guanidine that opens POTASSIUM CHANNELS producing direct peripheral vasodilatation of the ARTERIOLES. It reduces BLOOD PRESSURE and peripheral resistance and produces fluid retention. (Martindale The Extra Pharmacopoeia, 31st ed)
A heterogeneous, immature population of myeloid cells that can suppress the activity of T-CELLS and NATURAL KILLER CELLS in the INNATE IMMUNE RESPONSE and ADAPTIVE IMMUNE RESPONSE. They play important roles in ONCOGENESIS; INFLAMMATION; and INFECTION.
The retention of a denture in place by design, device, or adhesion.