The Story of CD4⁺CD28⁻T Cells Revisited: Solved or Still Ongoing?

Abstract

CD4+CD28− T cells are a unique type of proinflammatory T cells characterised by blockade of costimulatory CD28 receptor expression at the transcriptional level, which is still reversible by IL-12. In healthy individuals older than 65 years, these cells may accumulate to up to 50% of total CD4+ T lymphocytes as in many immune-mediated diseases, immunodeficiency, and specific infectious diseases. Here we focus on CD4+CD28− T cells in chronic immune-mediated diseases, summarizing various phenotypic and functional characteristics, which vary depending on the underlying disease, disease activity, and concurrent treatment. CD4+CD28− T cells present as effector/memory cells with increased replicative history and oligoclonality but reduced apoptosis. As an alternative costimulatory signal instead of CD28, not only natural killer cell receptors and Toll-like receptors, but also CD47, CTLA-4, OX40, and 4-1BB have to be considered. The proinflammatory and cytotoxic capacities of these cells indicate an involvement in progression and maintenance of chronic immune-mediated disease. So far it has been shown that treatment with TNF-α blockers, abatacept, statins, and polyclonal antilymphocyte globulins (ATG) mediates reduction of the CD4+CD28− T cell level. The clinical relevance of targeting CD4+CD28− T cells as a therapeutic option has not been examined so far.

CD28 Costimulation: From Mechanism to Therapy

“…CD4 + CD28 − cells are also elevated in diverse conditions including acute coronary syndrome, chronic kidney graft rejection, and cytomegalovirus infection. The cells produce interferon gamma and cytotoxic proteins perforin and granzyme B (Maly and Schirmer, 2015). Chronic antigenic stimulation may be associated with the loss of CD28 on CD4 + T cells since CMV responsiveness is 30-fold more common among CD4 + CD28 − cells than among CD4 + CD28 + cells (van Bergen et al, 2009).…”

Circulating CD4+CD28null and extra-thymic CD4+CD8+ double positive T cells are independently associated with disease damage in systemic lupus erythematosus patients

“…20 Furthermore, both cell populations behave similarly in ACPAþ RA patients, 8 and in patients with chronic infections like HIV; 17 moreover, it has been proposed that CD4þCD8þ DP T cells could originate from CD4þCD28null. 21 CD4þCD8þ DP T cells have a pro-inflammatory phenotype, including the production of pro-inflammatory cytokines like IFN-g, 8,[8][9][10][11][12][13][14][15][16][17][18][19][20][21] This subpopulation is associated with a higher level of TNF-a. 22 CD4þCD8þ DP T cells express CD56 and perforin, suggesting they have a cytotoxic capacity.…”

Inflammatory and metabolic markers and short-time outcome in patients with acute ischemic stroke in relation to TOAST subtypes

“…Other role of the local production of TNF-α in the immune response to the ischemic stroke is the downregulation of CD28 molecule (Liaskou et al 2014), contributing to the accumulation of CD4 + CD28 null T cells in the peripheral blood, an unusual subset of T lymphocytes with functional cytotoxic and inflammatory features, and enhanced expression of surface adhesion molecules that may predispose to vascular injury (Liuzzo et al 2007;Maly and Schirmer 2015). A positive correlation was observed between CD4+ CD28 null T cells and CRP levels in patients with recurrence of acute coronary events (Liuzzo et al 2007).…”