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T-bet Down-Modulation in Tolerized Th1 Effector CD4 Cells Confers a TCR-Distal Signaling Defect That Selectively Impairs IFN- Expression¹

Meixiao Long^*, Aaron M. Slaiby^*, Adam T. Hagymasi^*, Marianne A. Mihalyo^*, Alexander C. Lichtler, Steven L. Reiner and Adam J. Adler^2,*

^* Center for Immunotherapy of Cancer and Infectious Diseases and Department of Immunology, Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06030; and Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104

When Th1 effector CD4 cells encounter tolerizing Ag in vivo, their capacity to express the effector cytokines IFN- and TNF- is lost more rapidly than noneffector functions such as IL-2 production and proliferation. To localize the relevant intracellular signaling defects, cytokine expression was compared following restimulation with Ag vs agents that bypass TCR-proximal signaling. IFN- and TNF- expression were both partially rescued when TCR-proximal signaling was bypassed, indicating that both TCR-proximal and -distal signaling defects impair the expression of these two effector cytokines. In contrast, bypassing TCR-proximal signaling fully rescued IL-2 expression. T-bet, a transcription and chromatin remodeling factor that is required to direct the differentiation of naive CD4 cells into IFN--expressing Th1 effectors, was partially down-modulated in tolerized Th1 effectors. Enforcing T-bet expression during tolerization selectively rescued the ability to express IFN-, but not TNF-. Conversely, expression of a dominant-negative T-bet in Th1 effectors selectively impaired the ability to express IFN-, but not TNF-. Analysis of histone acetylation at the IFN- promoter further suggested that down-modulation of T-bet expression during Th1 effector CD4 cell tolerization does not impair IFN- expression potential through alterations in chromatin structure.

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