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TGF-β Inhibits IL-2 Production and Promotes Cell Cycle Arrest in TCR-Activated Effector/Memory T Cells in the Presence of Sustained TCR Signal Transduction¹

Lopamudra Das^* and Alan D. Levine^2,*,

^* Department of Medicine and Departments of Pathology, Pharmacology, and the Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106

TGF-β signaling is critical for controlling naive T cell homeostasis and differentiation; however, the biological and biochemical changes induced by TGF-β in effector/memory T cells are poorly defined. We show that although TGF-β inhibits effector/memory peripheral blood T lymphoblast proliferation and IL-2 production, the intensity and kinetics for TCR-induced global tyrosine phosphorylation are markedly increased compared with that in untreated cells or naive T cells. After TCR ligation, tyrosine phosphorylation of proximal tyrosine kinases and docking proteins like linker for activation of T cells is maintained for >30 min in TGF-β-primed cells compared with untreated cells where phosphorylation of these targets returned to basal levels by 10 min. Extended phosphorylation of linker for activation of T cells in treated peripheral blood T selectively prolongs ERK 1/2 signaling and phospholipase C-1 activation leading to increased Ca²⁺ flux. A kinase/phosphatase imbalance could not account for extended phosphorylation as CD45R, SHP-1, and SHP-2 expression remains unaltered. The contradiction between prolonged signal transduction and inhibition of proliferation is partially explained by the observation that TGF-β priming results in ERK 1/2-independent p21 induction and decreased cyclin D1 expression leading to accumulation of T cells in G₀/G₁ phases of the cell cycle and cell cycle arrest. Despite inhibition of T cell function by TGF-β priming, TCR and cytokine signaling pathways are intact and selectively extended, suggesting that suppression in the effector/memory T cell is mediated by reprogramming signal transduction, rather than its inhibition as in the naive T cell.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (DK-54213 and AI-53188; to A.D.L.) and the Crohn’s and Colitis Foundation of America (to L.D.).

² Address correspondence and reprint requests to Dr. Alan D. Levine, Department of Medicine, School of Medicine, Case Western Reserve University, Biomedical Research Building 425, 10900 Euclid Avenue, Cleveland, OH 44106-4952. E-mail address: alan.levine{at}case.edu

³ Abbreviations used in this paper: Treg, regulatory T cell; CDKI, cyclin-dependent kinase inhibitor; LAT, linker for activation of T cells; PLC, phospholipase C; SH2, Src homology 2; PTK, protein tyrosine kinase; PTP, protein tyrosine phosphatase; Grb, growth factor receptor-binding protein; PBT, peripheral blood T cell; ROS, reactive oxygen species.