Abstract
ObjectiveCo-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.Methods and ResultsTIGIT 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.ConclusionsDespite 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.
Highlights
Atherosclerosis, a chronic autoimmune-like disease, results from imbalanced pro- and anti-inflammatory responses, resulting in infiltration of inflammatory cells in the vessel wall
T cell immunoglobulin and ITIM domain (TIGIT) was upregulated on CD4+ T cells isolated from mice fed a Western-type diet in comparison with mice fed a chow diet
Elevated percentages of dendritic cells were observed in the blood and spleen of agonistic anti-TIGIT-treated mice
Summary
Atherosclerosis, a chronic autoimmune-like disease, results from imbalanced pro- and anti-inflammatory responses, resulting in infiltration of inflammatory cells in the vessel wall. This results in the formation of an atherosclerotic plaque and eventually causes plaque rupture. Immune responses are regulated by a network of costimulatory and coinhibitory molecules present on T cells and antigen presenting cells (APCs), such as macrophages and dendritic cells. The immune system provides a large diversity of costimulatory and coinhibitory pathways and each pathway has its own unique effect on the fate of individual immune cells. A new-emerging complex network of costimulatory and coinhibitory molecules is formed by T cell immunoreceptor with Ig and ITIM domains (TIGIT, Vstm, WUCAM), CD226 Costimulatory signals can promote T cell survival, cell cycle progression and differentiation to effector and memory T cells, whereas coinhibitory molecules can terminate these processes directly or indirectly via for example the induction of regulatory T cells (Tregs).
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