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1 Inhibits Ca2+-Calcineurin-Mediated Activation in Thymocytes 1
,
Departments of
*
Molecular Genetics, Biochemistry and Microbiology,
Pathology and Laboratory Medicine, and
Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267; and
Shriners Hospital for Children, Cincinnati, OH 45229
TGF
1 is a polypeptide growth modulatory and differentiation factor involved in many biological processes including immune homeostasis and self-tolerance. Tgfb1 knockout mice die around weaning age due to severe inflammation in most major organ systems, but the mechanism underlying this disease is not understood. In this study we demonstrate that Tgfb1-/- CD4+CD8+ and CD4+CD8- thymocytes are hyperresponsive to receptor-mediated and receptor-independent mitogenic stimulation. A suboptimal concentration of ionomycin in the presence of PMA fully activates Tgfb1-/- thymocytes, whereas the inhibitors of Ca2+ influx and calcineurin, EGTA and FK506, eliminate the hyperresponsiveness. Hence, the hypersensitivity of Tgfb1-/- thymocytes is due to a lowered threshold for Ca2+-dependent activation. Further, we demonstrate that the hypersensitivity of thymocytes results from the absence of TGF1 and not from the inflammatory environment because the thymocytes are hyperresponsive in preinflammatory-stage Tgfb1-/- mice. Our results suggest for the first time that TGF1 functions to inhibit aberrant T cell expansion by maintaining intracellular calcium concentration levels low enough to prevent a mitogenic response by Ca2+-independent stimulatory pathways alone. Consequently, TGF1 prevents autoimmune disease through a Ca2+ regulatory pathway that maintains the activation threshold above that inducible by self-MHC-TCR interactions.
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