Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells

Abstract

The suppressive effects of CD4+CD25+ regulatory T cells (Tregs) on T cells have been well documented. Here we investigated whether human CD4+CD25+ Tregs can inhibit the proinflammatory properties of monocytes/macrophages. Monocytes and T cells were isolated from peripheral blood of healthy volunteers by magnetic cell separation and cocultured for 40 h. Monocytes were analyzed directly for cytokine production and phenotypic changes or repurified and used in T-cell stimulation and lipopolysaccharide challenge assays. Coculture with CD4+CD25+ Tregs induced minimal cytokine production in monocytes, whereas coculture with CD4+CD25- T cells resulted in large amounts of proinflammatory (tumor necrosis factor-alpha, interferon-gamma, interleukin-6) and regulatory (interleukin-10) cytokines. Importantly, when these CD4+CD25+ Treg-treated monocytes were repurified after coculture and challenged with lipopolysaccharide, they were severely inhibited in their capacity to produce tumor necrosis factor-alpha and interleukin-6 compared with control-treated monocytes. In addition, monocytes that were precultured with CD4+CD25+ Tregs displayed limited upregulation of human leukocyte antigen class II, CD40 and CD80, and downregulation of CD86 compared with control-treated monocytes. This altered phenotype had functional consequences, as shown by the reduction in T cell-stimulatory capacity of Treg-treated monocytes. Together, these data demonstrate that CD4+CD25+ Tregs can exert direct suppressive effects on monocytes/macrophages, thereby affecting subsequent innate and adaptive immune responses.

Higher expression of Bax in regulatory T cells increases vascular inflammation

“…Correlating with the thickened vessel wall, the infiltrated inflammatory cells in the vessel from Bax Tg after cuff placement were significantly higher than that in wild-type mice ( Figure 6C4). Since it has been reported that CD4+CD25+ Tregs can exert direct suppressive effects on monocytes/macrophages in addition to suppressing effector T cells (33), therefore, our results suggest that the higher expression of Bax in Tregs reduces the striking threshold of inflammatory pathogenesis of vasculitis due to higher rates of Treg apoptosis and presumably failure in suppressing inflammatory cells ( Figure 6D). …”

Proinflammatory mediator–induced reversal of CD4+,CD25+ regulatory T cell–mediated suppression in rheumatoid arthritis

“…CD4ϩ,CD25ϩ Treg cells have been shown to inhibit T cell proliferation, cytokine production, autoantibody production, and dendritic cell and monocyte/ macrophage function (1)(2)(3)(4)(5)(6). Recent studies suggest that their function is defective in certain human autoimmune diseases (7), including multiple sclerosis (8), type 1 diabetes mellitus (9), and rheumatoid arthritis (RA) (10).…”

CD4+/FOXP3+ Regulatory T Cells in End-Stage Kidney Disease: Molecular Pathways Trough Cell-Cycle Arrest and Apoptosis

“…Indeed, recent findings indicate, that these M/M are also able to induce Tregs, which additionally account for the drastically reduced T cell proliferation induced by the M/M [45]. Vice versa, Tregs respond to M/M since they are able to block M/M maturation [46]. Thus, these data indicate that alternatively activated M/M can induce immunosuppressive Tregs and that in return these Tregs are potent suppressors of M/M maturation.…”