IL-2 Overcomes the Unresponsiveness but Fails to Reverse the Regulatory Function of Antigen-Induced T Regulatory Cells

Abstract

Intranasal administration of peptide Ac1–9[4Y], based on the N-terminal epitope of myelin basic protein, can induce CD4+ T cell tolerance, and suppress experimental autoimmune encephalomyelitis induction. The peptide-induced regulatory T (PI-TReg) cells failed to produce IL-2, but expressed IL-10 in response to Ag and could suppress naive T cell responses in vitro. Analysis of Jak-STAT signaling pathways revealed that the activation of Jak1, STAT3, and STAT5 were induced in tolerant T cells after Ag stimulation in vivo. In addition, the expression of suppressor of cytokine signaling 3 was induced in tolerant T cells, suggesting that cytokines regulate the tolerant state of the PI-TReg cells. Stimulation of PI-TReg cells in vitro with IL-10 induced Jak1 and STAT3 activation, but not STAT5, suggesting that IL-10 is important, but not the only cytokine involved in the development of T cell tolerance. Although IL-2 expression was deficient, stimulation with IL-2 in vitro induced Jak1 and STAT5 activation in PI-TReg cells, restored their proliferative response to antigenic stimulation, and abrogated PI-TReg-mediated suppression in vitro. However, the addition of IL-2 could not suppress IL-10 expression, and the IL-2 gene remained inactive. After withdrawal of IL-2, the PI-TReg cells regained their nonproliferative state and suppressive ability. These results underline the ability of the immune system to maintain tolerance to autoantigens, but at the same time having the ability to overcome the suppressive phenotype of tolerant T cells by cytokines, such as IL-2, during the protective immune response to infection.

IL-2–Engineered nano-APC Effectively Activates Viral Antigen-Mediated T Cell Responses from Chronic Hepatitis B Virus-Infected Patients

“…After repeated Ag stimulation, effector T cells become tolerant (12). We found that tolerance is not due to loss of Ag-specific T cells, but rather downregulation of proximal TCR signaling pathways following Ag stimulation (13,14), which resembles the findings from chronic viral infections (4). We found that an increase in the amount of Ag presented by activated dendritic cells (DC) cannot reverse tolerance (13).…”

“…We found that tolerance is not due to loss of Ag-specific T cells, but rather downregulation of proximal TCR signaling pathways following Ag stimulation (13,14), which resembles the findings from chronic viral infections (4). We found that an increase in the amount of Ag presented by activated dendritic cells (DC) cannot reverse tolerance (13). However, addition of IL-2 can effectively overcome tolerance and restore the full activation of T cells in response to Ag stimulation (13).…”

“…We found that an increase in the amount of Ag presented by activated dendritic cells (DC) cannot reverse tolerance (13). However, addition of IL-2 can effectively overcome tolerance and restore the full activation of T cells in response to Ag stimulation (13). It has been found that liver sinusoidal endothelial cells can induce tolerance of HBVspecific CD8 T cells through interaction between B7-H1 on liver sinusoidal endothelial cells and programmed cell death-1 on CD8 T cells, and such tolerance can be effectively overcome by IL-2 (15).…”

The immunosuppressive drug FK778 induces regulatory activity in stimulated human CD4+CD25− T cells

“…The relatively high degree of STAT3 phosphorylation is in line with recent data indicating that increased levels of STAT3 protein are a feature of allotolerant cells, 28 and that signaling via the immunosuppressive cytokine IL-10 requires STAT3 activation. 29,30 The phenotype of the Treg cells induced by FK778 was further characterized by the presence of CD45RO and lack of CD27 and CD62L expression. This fits an effector-memory phenotype, making these cells suitable to act at a site of inflammation.…”

Developing a Rational Tumor Vaccine Therapy for Renal Cell Carcinoma: Immune Yin and Yang

“…Under experimental conditions in murine models, tumor-DC vaccinations can overcome tolerance and enhance therapeutic outcome (24). IL-2 and IFN-a can also contribute in overcoming these regulatory pathways (25,26). Other inhibitory loops include both natural killer T cells and a subpopulation of inhibitory DCs (27,28).…”