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* Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, United Kingdom;
Tumor Immunology, Lund University, Lund, Sweden;
Department of Biological Sciences, Brunel University, Uxbridge, London, United Kingdom; and
Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, Bristol, United Kingdom
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.
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