The Complex Role of T-Cells in Atherosclerosis: Cholesterol Accumulation, Differentiation and Aging

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Atherosclerosis, a chronic inflammatory disease of the arteries, is a leading cause of cardiovascular diseases (CVD) worldwide. While the role of immune cells in atherosclerosis has been extensively studied, recent research has shed light on the intricate involvement of T-cells in this process.

T-cells, a crucial component of the immune system, make up a significant portion of leukocytes in advanced human atherosclerotic lesions. In this article, we will explore the multifaceted role of T-cells in atherosclerosis, focusing on their interactions, differentiation, cholesterol accumulation, and aging.

T-Cell Interactions in Atherosclerosis

T-cells play a central role in atherosclerosis by interacting with other immune cells, including macrophages and dendritic cells (DCs), upon infiltrating atherosclerotic lesions. These interactions are initiated when T-cells recognize specific antigens presented by DCs.

Depending on the cytokine milieu, naive T-cells differentiate into distinct subsets, such as T regulatory cells (Tregs), T helper 1 (Th1) cells, Th2 cells, Th17 cells, and T follicular helper (Tfh) cells, each characterized by unique transcription factors.

Studies have shown that more than 80% of T-cells in atherosclerotic plaques express CD44, indicating their antigen-experienced status. Antigens presented to T-cells in atherosclerotic lesions include apolipoprotein B100 (apoB100), low-density lipoprotein (LDL), and oxidized LDL.

Initially, it was believed that antigen presentation in plaques induced the production of pro-atherogenic Th1 cytokines like interferon γ (IFNγ) and tumor necrosis factor α (TNFα). However, later studies revealed an expansion of Tregs in response to antigens, exerting an anti-atherogenic role by secreting interleukin (IL)-10 and transforming growth factor β (TGF-β), which induce processes like smooth muscle cell (SMC) migration and collagen production.

Recent single-cell RNA sequencing (sc-RNA-Seq) studies have uncovered a high diversity of T-cells in atherosclerotic plaques, further highlighting the complexity of their role in atherosclerosis. Although individual T-cell subsets can have either pro- or anti-atherogenic effects based on the cytokines they secrete, complete ablation of CD4+ or CD8+ T-cells has been shown to reduce atherosclerosis, emphasizing the intricate nature of T-cell involvement in atherogenesis.

Cholesterol Accumulation in T-Cells

Cholesterol metabolism plays a critical role in T-cell function and atherosclerosis. T-cells express cholesterol transporters, including ATP Binding Cassette A1 (ABCA1) and ATP Binding Cassette G1 (ABCG1), which facilitate cholesterol efflux to apolipoprotein A-I (apoA-I) and high-density lipoprotein (HDL), respectively. Cholesterol accumulation primarily occurs in T-cell plasma membranes, crucial for T-cell receptor (TCR) signaling and proliferation in response to antigen interactions.

TCR stimulation, mimicked by anti-CD3, leads to decreased expression of cholesterol transporters ABCA1 and ABCG1, primarily due to the suppression of Liver X receptor (LXR) signaling. TCR stimulation also increases the expression of enzymes that promote cholesterol synthesis, uptake, and esterification. Cholesterol accumulation is vital for T-cell proliferation, as evidenced by studies showing that cholesterol depletion or inhibition of cholesterol synthesis results in a loss of T-cell proliferation.

T-Cell Cholesterol Accumulation and Aging

Aging and cardiovascular disease can impact T-cell functionality and cholesterol metabolism. Aged T-cells tend to accumulate cholesterol, and recent studies suggest that T-cell cholesterol accumulation may contribute to apoptosis, which impairs T-cell proliferation and responses to antigens. Furthermore, T-cells from patients with cardiovascular disease lose their proliferative capacity, possibly due to excessive cholesterol accumulation and subsequent apoptosis.

Notably, T-cell Abca1/Abcg1 deficiency, which increases membrane cholesterol accumulation, was found to have age-dependent effects. While it increased T-cell proliferation in young mice, it almost abolished T-cell proliferation in aged mice, possibly due to senescence and increased apoptosis in aged T-cells. Cholesterol accumulation in T-cells also plays a role in cardiovascular diseases, with advanced coronary artery disease (CAD) patients showing decreased T-cell proliferation and increased apoptosis compared to those with early CAD, irrespective of age.

Cholesterol Accumulation and T-Cell Differentiation

Cholesterol accumulation in T-cells can influence their differentiation into cytotoxic T-cells. Increased membrane cholesterol promotes the differentiation of CD8+ T-cells into cytotoxic cells, which are essential for immune defense. Conversely, cholesterol depletion or inhibition of cholesterol synthesis reduces this differentiation.

In atherosclerosis, Tregs, which usually have an atheroprotective role, can undergo a phenotypic switch, acquiring markers of pro-atherogenic Th1, Th17, and Tfh cells. This switch may be cholesterol-dependent, and cholesterol accumulation in Tregs compromises their function. Recent studies using fluorescent tracing techniques have confirmed that Tregs can switch phenotypes during atherosclerosis.

Discussion

The discussion of T-cell membrane cholesterol accumulation in the context of T-cell function, aging, and cardiovascular diseases raises intriguing questions and opens avenues for future research.

Mechanisms Underlying T-Cell Cholesterol Accumulation

The exact mechanisms underlying T-cell cholesterol accumulation and its impact on T-cell function remain areas of active investigation. While it is clear that membrane cholesterol accumulation is crucial for T-cell proliferation and differentiation into cytotoxic T-cells downstream of T-cell receptor (TCR) signaling, the precise molecular events involved require further elucidation. One hypothesis suggests that membrane cholesterol accumulation may induce TCR clustering, thereby enhancing TCR signaling. However, conflicting data from studies employing artificial membranes indicate that more research is needed to fully understand the role of membrane cholesterol in TCR signaling. Future studies should focus on unraveling the molecular details of this process.

Cholesterol Accumulation, Aging, and T-Cell Function

The interplay between cholesterol accumulation, aging, and T-cell function raises important questions about the mechanisms driving T-cell decline in older individuals. As T-cells accumulate cholesterol with age, it is essential to explore whether cholesterol-induced T-cell apoptosis or exhaustion is a primary driver of the decline in T-cell numbers. Understanding the molecular pathways involved in these processes may provide insights into strategies to counteract age-related declines in immune function.

Moreover, the diminished T-cell functionality observed in patients with advanced coronary artery disease (CAD) may indeed be linked to T-cell cholesterol accumulation. Investigating the relationship between cholesterol levels in T-cells from CAD patients and their T-cell function can offer valuable clinical insights. Future research should aim to establish a direct causal link between cholesterol accumulation and impaired T-cell functionality in cardiovascular diseases.

T-Cell Cholesterol Accumulation and Atherosclerotic Plaques

The presence of T-cells in atherosclerotic plaques and their differentiation into specific subsets within the plaque environment underscores the complexity of T-cell involvement in atherosclerosis. While the local plaque environment seems to influence T-cell differentiation, the precise triggers and regulatory mechanisms remain elusive. Recent studies using single TCR sequencing suggest the presence of autoreactive CD4+ T-cells, pointing toward an autoimmune component in atherosclerosis.

Future investigations should focus on identifying the specific triggers and molecular pathways governing T-cell subset differentiation within atherosclerotic plaques. Understanding these mechanisms could offer new therapeutic targets for modulating T-cell behavior and potentially mitigating the progression of atherosclerosis.

Implications for Immune Responses

T-cell membrane cholesterol accumulation emerges as a critical regulator of peripheral T-cell functionality, particularly in response to infections. The finding that a lack of cholesterol synthesis in CD8+ T-cells results in attenuated clonal T-cell expansion during viral infection underscores the importance of cholesterol homeostasis in immune responses. Further research into the role of cholesterol in different types of infections and immune responses could have significant implications for vaccine development and immunotherapy.

Conclusion

In conclusion, T-cell membrane cholesterol accumulation plays a pivotal role in regulating T-cell function, impacting proliferation, differentiation, and immune responses. Understanding the underlying mechanisms and their implications for aging and cardiovascular diseases is crucial for developing targeted therapeutic strategies. Future research efforts should aim to uncover the precise molecular pathways involved and explore potential interventions to modulate T-cell cholesterol accumulation and function. This knowledge may have broader implications for immune-related disorders and therapeutic interventions beyond atherosclerosis and cardiovascular diseases.


reference link : 10.1007/s11883-023-01125-y

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