Targeting T cells to treat atherosclerosis: odyssey from bench to bedside

Abstract

More than 150 years from the initial description of inflammation in atherosclerotic plaques, randomized clinical trials to test anti-inflammatory therapies in atherosclerosis have recently been initiated. Lymphocytes and macrophages are main participants in the inflammatory response in atherosclerosis. T lymphocytes operate mainly by exerting strong influences on the function of many cells in the immune system and beyond, and co-ordinating their interactions. Importantly, T lymphocytes are not a homogenous population, but include several subsets with specialized functions that can either promote or suppress inflammation. The interactions between these T-lymphocyte subsets have critical consequences on the course and outcome of inflammation. The complexity of the inflammatory response in atherosclerosis poses significant challenges on translating experimental findings into clinical therapies and makes the journey from bench to bedside an arduous one. Here, we summarize recent advances on the role of CD4(+) T cells in the inflammatory process in atherosclerosis and discuss potential therapies to modulate these lymphocytes that may provide future breakthroughs in the treatment of atherosclerosis.

Keywords: Atherosclerosis; Immune response; Immunomodulation; Inflammation; T lymphocytes.

Figure 1

Overview of cardinal features and potential strategies to target CD28^null and regulatory T-cell lymphocytes in atherosclerosis. CD28^null T cells expand in the circulation and atherosclerotic plaques in patients with acute coronary syndrome. These cells produce high levels of inflammatory cytokines (interferon-γ and tumour necrosis factor-α) and express and release cytotoxic molecules (perforin and granzyme B). The production of cytokines and cytotoxic molecules is modulated by co-stimulatory receptors OX40 and 4-1BB, which are up-regulated on CD28^null T cells. Moreover, CD28^null T cells are resistant to apoptosis due to reduction in apoptotic molecules Fas, Bim, and Bax, which underlies the expansion of this cell subset in acute coronary syndrome patients. Several strategies have been proposed to reduce the number and/or function of CD28^null T cells such as tumour necrosis factor-α inhibition, statins, sensitization to apoptosis, and inhibition of co-stimulation (CTLA4-Ig, anti-OX40, and anti-4-1BB antibodies). Regulatory T cells have crucial roles in counteracting the actions of inflammatory T lymphocytes such as CD28^null T cells. Redundant mechanisms enable regulatory T cells to suppress inflammation and T-cell actions among which are the production of anti-inflammatory cytokines (interleukin-10 and transforming growth factor-β), CTLA-4-mediated suppression, and interference with metabolic pathways (conversion of ATP into adenosine, which has anti-inflammatory properties). On-going experimental and clinical work is testing various strategies to boost the number and/or the function of circulating or intraplaque regulatory T cells such as adoptive transfer of regulatory T cells expanded in vitro, vaccination protocols that induce expansion of naturally occurring regulatory T cells or conversion of conventional CD4⁺ T cells into regulatory T cells, and blockade of inflammatory cytokines (tumour necrosis factor-α and interleukin-6).