Uncoupling of IL-2 Signaling from Cell Cycle Progression in Naive CD4+ T Cells by Regulatory CD4+CD25+ T Lymphocytes

Abstract

Prior reports have shown that CD4+CD25+ regulatory T cells suppress naive T cell responses by inhibiting IL-2 production. In this report, using an Ag-specific TCR transgenic system, we show that naive T cells stimulated with cognate Ag in the presence of preactivated CD4+CD25+ T cells also become refractory to the mitogenic effects of IL-2. T cells stimulated in the presence of regulatory T cells up-regulated high affinity IL-2R, but failed to produce IL-2, express cyclins or c-Myc, or exit G0-G1. Exogenous IL-2 failed to break the mitotic block, demonstrating that the IL-2 production failure was not wholly responsible for the proliferation defect. This IL-2 unresponsiveness did not require the continuous presence of CD4+CD25+ regulatory T cells. The majority of responder T cells reisolated after coculture with regulatory cells failed to proliferate in response to IL-2, but were not anergic and proliferated in response to Ag. The mitotic block was also dissociated from the antiapoptotic effects of IL-2, because IL-2 still promoted the survival of T cells that had been cocultured with CD4+CD25+ T cells. IL-2-induced STAT5 phosphorylation in the cocultured responder cells was intact, implying that the effects of the regulatory cells were downstream of receptor activation. Our results therefore show that T cell activation in the presence of CD4+CD25+ regulatory T cells can induce an alternative stimulation program characterized by up-regulation of high affinity IL-2R, but a failure to produce IL-2, and uncoupling of the mitogenic and antiapoptotic effects of IL-2.

The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease

“…Despite suggestions that Tregs influence cells by direct contact, these cell-to-cell interactions are poorly mapped. Indeed, there is evidence that some of the activity of Tregs progresses through intermediaries, such as NK T [176] and mast cells [177], and that their effect on target T effector cells includes an arrest in cell cycle progression caused by uncoupling of IL-2 signalling [178,179]. Recently, a role for IFN-g in the regulatory function of Tregs has also been proposed based on the up-regulation of IFN-g mRNA in alloantigen-reactive Tregs in vivo hours after encounter with antigen and failure of skin graft tolerance in the presence of IFN-g neutralization [180].…”

Human Umbilical Cord Mesenchymal Stem Cells Suppress Systemic Lupus Erythematosus Lesions by Rebalancing CD4+/CD8+ Cell Population

“…The best characterized Treg cells, a subset of CD4+ T-helper cells expressing high levels of the interleukin-2 receptor α-chain CD25 and the transcription factor forkhead box P3 (FoxP3) [37], have the ability to suppress CD8+ T cells and NK cells, to inhibit aberrant immune responses, to regulate peripheral T-cell homeostasis, and to maintain self-tolerance by secreting immunoregulation factors such as IL-4, IL-10 and TGF-β [38][39][40]. Unbalanced CD4+ cell population, like decreased CD4+CD25+ or increased CD4+CD25-can lead to the disorder of Th1/Th 2 and CD4+/CD8+ ratio, resulting in hyperfunction of humoral immunity, as in the case of SLE [41][42][43]. Recently, CD8+T-cell populations have also been shown to possess immunosuppressive function, including CD8+CD28-, CD8+IL-10+ and CD8+CD25+ T cells, which can inhibit the activation and proliferation of lymphocytes [44].…”

Mast Cells Down-Regulate CD4+CD25+ T Regulatory Cell Suppressor Function via Histamine H1 Receptor Interaction

“…Ϫ T resp cells (29), as well as interfering with IL-2R signal transduction (30). In this regard, it is noteworthy that the suppressor function of T reg cells is programmed by the Foxp3 transcription factor (5, 6), which also controls constitutive expression of CD25 by T reg cells (6,31,32).…”