TGF beta 1 Inhibits Ca super(2+)-Calcineurin-Mediated Activation in Thymocytes

• Published in: The Journal of immunology (1950) 2003-04, Vol.170 (7), p.3645-3652
• Main Authors: Bommireddy, R, Ormsby, I, Yin, M, Boivin, G P, Babcock, G F, Doetschman, T
• Format: Article
• Language: English
• ISSN: 0022-1767

TGF beta 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 super(-/-) CD4 super(+)CD8 super(+) and CD4 super(+)CD8 super(-) thymocytes are hyperresponsive to receptor-mediated and receptor-independent mitogenic stimulation. A suboptimal concentration of ionomycin in the presence of PMA fully activates Tgfb1 super(-/-) thymocytes, whereas the inhibitors of Ca super(2+) influx and calcineurin, EGTA and FK506, eliminate the hyperresponsiveness. Hence, the hypersensitivity of Tgfb1 super(-/-) thymocytes is due to a lowered threshold for Ca super(2+)-dependent activation. Further, we demonstrate that the hypersensitivity of thymocytes results from the absence of TGF beta 1 and not from the inflammatory environment because the thymocytes are hyperresponsive in preinflammatory-stage Tgfb1 super(-/-) mice. Our results suggest for the first time that TGF beta 1 functions to inhibit aberrant T cell expansion by maintaining intracellular calcium concentration levels low enough to prevent a mitogenic response by Ca super(2+)-independent stimulatory pathways alone. Consequently, TGF beta 1 prevents autoimmune disease through a Ca super(2+) regulatory pathway that maintains the activation threshold above that inducible by self-MHC-TCR interactions.