Agonistic anti-TIGIT treatment inhibits T cell responses in LDLr deficient mice without affecting atherosclerotic lesion development

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Abstract

OBJECTIVE: Co-stimulatory and co-inhibitory molecules are mainly expressed on T cells and antigen presenting cells and strongly orchestrate adaptive immune responses. Whereas co-stimulatory molecules enhance immune responses, signaling via co-inhibitory molecules dampens the immune system, thereby showing great therapeutic potential to prevent cardiovascular diseases. Signaling via co-inhibitory T cell immunoglobulin and ITIM domain (TIGIT) directly inhibits T cell activation and proliferation, and therefore represents a novel therapeutic candidate to specifically dampen pro-atherogenic T cell reactivity. In the present study, we used an agonistic anti-TIGIT antibody to determine the effect of excessive TIGIT-signaling on atherosclerosis.<br /><br />METHODS AND RESULTS: TIGIT was upregulated on CD4(+) T cells isolated from mice fed a Western-type diet in comparison with mice fed a chow diet. Agonistic anti-TIGIT suppressed T cell activation and proliferation both in vitro and in vivo. However, agonistic anti-TIGIT treatment of LDLr(-/-) mice fed a Western-type diet for 4 or 8 weeks did not affect atherosclerotic lesion development in comparison with PBS and Armenian Hamster IgG treatment. Furthermore, elevated percentages of dendritic cells were observed in the blood and spleen of agonistic anti-TIGIT-treated mice. Additionally, these cells showed an increased activation status but decreased IL-10 production.<br /><br />CONCLUSIONS: Despite the inhibition of splenic T cell responses, agonistic anti-TIGIT treatment does not affect initial atherosclerosis development, possibly due to increased activity of dendritic cells.

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Foks, A. C., Ran, I. A., Frodermann, V., Bot, I., Van Santbrink, P. J., Kuiper, J., & Van Puijvelde, G. H. M. (2013). Agonistic anti-TIGIT treatment inhibits T cell responses in LDLr deficient mice without affecting atherosclerotic lesion development. PLoS ONE, 8(12). https://doi.org/10.1371/journal.pone.0083134

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