Increased Expression of T Cell Immunoglobulin- and Mucin Domain-containing Molecule-3 on Natural Killer Cells in Atherogenesis

Objective: Atherosclerosis (AS) has many features of a chronic inflammatory disease in which both adaptive and innate immune cells play roles. Increasing evidence has demonstrated the impairment of circulating natural killer (NK) cells in atherosclerosis. However, the mechanisms of this impairment remain unclear. We previously reported the suppression of NK cell functions by T cell immunoglobulin- and mucin domain-containing molecule (Tim)-3. Here, we investigated the expression of Tim-3 on NK cells and assessed its possible roles in NK loss during atherogenesis.

Methods And Results: Flow cytometry analysis showed increased Tim-3 expression on peripheral NK cells from patients with AS. This increased expression of Tim-3 was significantly related to the levels of serum lipids and inflammation markers, C-reactive protein (CRP) and tumor necrosis factor (TNF)-α, which are risk factors for atherogenesis. We detected decreased peripheral NK cell number in patients with AS. The NK cell number showed significant inverse correlations with Tim-3 expression levels on NK cells and the level of serum TNF-α. Consistently, Tim-3 overexpression reduced NK92 cell number. Blockade of Tim-3 protected NK92 cells from TNF-α-induced cell death. Similar results were obtained with peripheral NK cells from patients with AS.

Conclusions: To the best of our knowledge, for the first time, the data from our study provide evidence that augmented Tim-3 expression on NK cells plays an important role in NK cell loss in atherosclerosis. The augmented Tim-3 expression on NK cells might be used as an indicator for disease progression.