A Critical Role for Stat3 Signaling in Immune Tolerance

Immunity 2003, 19: 425-436.

Speaker: 吳育欣                            Time: 14:00-15:00 11/12/2003

Commentator: 劉校生老師                    Place: Room 601

Abstract

     Antigen-presenting cells (APCs) are at the center of a critical decision leading to immune activation versus immune tolerance. Previous studies have shown the state of activation/differentiation of the APC at the time of antigen presentation is the central determinant of T cell priming versus tolerance, however, the intracellular signaling pathways in these APCs remains to be elucidated. Recently one of the members of the signal transducer and activators of transcription family, Stat3, has emerged as a negative regulator of inflammatory responses. In this study, the authors evaluate, therefore, whether Stat3 signaling may play a role in the ability of APCs to determine T cell response. The authors used tryphostin AG490, a compound known to block Stat3 activation in cells, to treat peritoneal elicited macrophages (PEM) and dendritic cells and found it can enhance antigen-presenting cell function. On the contrary, activation of Stat3 by IL-10 in APCs resulted in impaired antigen-specific T cell response. PEM from LysMcre/Stat3^flox/- mutant mice (mice in which macrophages are genetically devoid of Stat3) can efficiently prime naïve antigen-specific T cells and restore the responsiveness of tolerant T cells. This lack of Stat3 activity in PEM from LysMcre/Stat3^flox/- mice was associated with an increased activity of the proinflammatory Stat1 signaling pathway. When injecting a tolerogenic dose of peptide to these mice, it leads to T cell activation rather than tolerance, which may be due to an increase of IL-12 and RANTES production by Stat3^-/-PEM. Further studies on phenotypic characteristics and the cytokine/chemokine profile of Stat3^-/- PEM showed an increased expression of MHC class Ⅱ molecules, B7.1 and B7.2 costimulatory molecules, and IL-12; while there was no IL-10 can be detected. Taken together, Stat3 signaling provides a novel molecular target for manipulation of immune activation/ tolerance, a central decision with profound implications in autoimmunity, transplantation, and cancer immunotherapy.

References

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2.     Steinman, K., et al 2003. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685-711