Unusual CD4⁺CD28⁻T Cells and Their Pathogenic Role in Chronic Inflammatory Disorders

Abstract

CD28 is a primary co-stimulatory receptor that is essential for successful T cell activation, proliferation, and survival. While ubiquitously expressed on naive T cells, the level of CD28 expression on memory T cells is largely dependent on the T-cell differentiation stage in humans. Expansion of circulating T cells lacking CD28 was originally considered a hallmark of age-associated immunological changes in humans, with a progressive loss of CD28 following replicative senescence with advancing age. However, an increasing body of evidence has revealed that there is a significant age-inappropriate expansion of CD4+CD28− T cells in patients with a variety of chronic inflammatory diseases, suggesting that these cells play a role in their pathogenesis. In fact, expanded CD4+CD28− T cells can produce large amounts of proinflammatory cytokines such as IFN-γ and TNF-α and also have cytotoxic potential, which may cause tissue damage and development of pathogenesis in many inflammatory disorders. Here we review the characteristics of CD4+CD28− T cells as well as the recent advances highlighting the contribution of these cells to several disease conditions.

Strain differences in thymic atrophy in rats immunized for EAE correlate with the clinical outcome of immunization

“…Considering that the development of inflammatory autoimmune diseases is associated with increased circulating TNF-α levels and that this cytokine directly downregulates CD28 expression on CD4+ T cells [ 23 , 24 , 52 ], the level of circulating TNF-α was also determined. Consistent with the increased frequency of CD28- cells within CD4+ T-PBLs of immunized DA rats, the circulating level of TNF-α in these animals increased (p<0.05) upon immunization, while it remained unaltered in AO rats ( Fig 10C ).…”

“…It should also be pointed that development of inflammatory autoimmune diseases leads to a premature decline in thymopoietic efficiency [ 21 , 22 ] and loss of CD28 expression on CD4+ T cells, reflecting not only a reduced thymopoiesis, but also a direct inhibitory action of proinflammatory cytokines on its expression [ 23 , 24 ]. These pathogenetic events, in turn, contribute to perpetuation of these diseases [ 21 – 24 ].…”

“…These pathogenetic events, in turn, contribute to perpetuation of these diseases [ 21 – 24 ]. Thus, the rise in the frequency of CD4+CD28- T cells has been proposed as a biomarker of not only chronobiological, but also of „premature aging”of the immune system under such pathological conditions [ 23 , 24 ]. Moreover, it was shown that the frequency of CD4+CD28- cells (exhibiting persistent activation and memory T cell phenotype) in peripheral blood correlates with the clinicopathological features of inflammatory autoimmune diseases [ 25 ].…”

“…Moreover, it was shown that the frequency of CD4+CD28- cells (exhibiting persistent activation and memory T cell phenotype) in peripheral blood correlates with the clinicopathological features of inflammatory autoimmune diseases [ 25 ]. It should be noted that most studies on CD4+CD28- T cells have been conducted in humans and that development of appropriate animal models is required in order to investigate the underlying mechanisms of this phenomenon and its biological relevance in vivo [ 23 ].…”

“…Additionally, to elucidate the putative mechanisms underlying thymopoietic changes, thymic tissue was examined for the expression of molecules regulating thymocyte precursor cell entry into the thymus (CXCL12) [ 45 ], their survival and differentiation/maturation (IL-7, IL-6) [ 46 – 49 ], and differentiation/maturation of CD4+ nTregs (IL-2, IL-15) [ 50 ]. Moreover, the circulating level of the proinflammatory cytokines IL-6 (associated with the decline in the efficacy of thymopoiesis [ 49 ]) and TNF-α, which is shown to induce not only thymic atrophy [ 51 ], but also loss of CD28 expression on CD4+ T cells [ 23 , 24 , 52 ] was investigated.…”