The life (and death) of CD4+ CD28(null) T cells in inflammatory diseases

Abstract

Inflammation contributes to the development and perpetuation of several disorders and T lymphocytes orchestrate the inflammatory immune response. Although the role of T cells in inflammation is widely recognized, specific therapies that tackle inflammatory networks in disease are yet to be developed. CD4(+) CD28(null) T cells are a unique subset of helper T lymphocytes that recently shot back into the limelight as potential catalysts of inflammation in several inflammatory disorders such as autoimmunity, atherosclerosis and chronic viral infections. In contrast to conventional helper T cells, CD4(+) CD28(null) T cells have an inbuilt ability to release inflammatory cytokines and cytotoxic molecules that can damage tissues and amplify inflammatory pathways. It comes as no surprise that patients who have high numbers of these cells have more severe disease and poor prognosis. In this review, I provide an overview on the latest advances in the biology of CD4(+) CD28(null) T cells. Understanding the complex functions and dynamics of CD4(+) CD28(null) T cells may open new avenues for therapeutic intervention to prevent progression of inflammatory diseases.

Keywords: CD4+CD28null T lymphocytes; apoptosis; atherosclerosis; autoimmunity; co-stimulation; helper T cells; inflammation.

© 2015 John Wiley & Sons Ltd.

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Figure 1

Characteristics of CD4+CD28null T cells in atherosclerosis. In patients that develop myocardial infarction due to coronary atherosclerosis CD4+CD28null T cells have features that distinguish them from conventional helper CD4+CD28+ T lymphocytes. Specifically, CD4+CD28null T cells express higher levels of alternative co-stimulatory receptors OX40 and 4-1BB, whereas co-inhibitory receptors (CTLA-4 and PD-1) are present in similar levels to those on CD28+ counterparts. OX40 and 4-1BB regulate the production of inflammatory cytokines [tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)] and the release of cytotoxic molecules (perforin, granzymes) by CD4+CD28null T cells. Moreover, in these patients the expression of the death receptor Fas and of pro-apoptotic mitochondrial proteins Bim and Bax is significantly reduced in CD4+CD28null T cells. This endows CD4+CD28null T lymphocytes with resistance to apoptosis, which may allow these cells to accumulate and amplify inflammation and cause vessel wall damage, which may contribute to atherosclerotic plaque rupture.