TGF beta 1 inhibits Ca2+-calcineurin-mediated activation in thymocytes.
TGFbeta1 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 Ca(2+) influx and calcineurin, EGTA and FK506, eliminate the hyperresponsiveness. Hence, the hypersensitivity of Tgfb1(-/-) thymocytes is due to a lowered threshold for Ca(2+)-dependent activation. Further, we demonstrate that the hypersensitivity of thymocytes results from the absence of TGFbeta1 and not from the inflammatory environment because the thymocytes are hyperresponsive in preinflammatory-stage Tgfb1(-/-) mice. Our results suggest for the first time that TGFbeta1 functions to inhibit aberrant T cell expansion by maintaining intracellular calcium concentration levels low enough to prevent a mitogenic response by Ca(2+)-independent stimulatory pathways alone. Consequently, TGFbeta1 prevents autoimmune disease through a Ca(2+) regulatory pathway that maintains the activation threshold above that inducible by self-MHC-TCR interactions.
Bommireddy
Ramireddy
R
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0524, USA.
Ormsby
Ilona
I
Yin
Moying
M
Boivin
Gregory P
GP
Babcock
George F
GF
Doetschman
Thomas
T
D000818:Animals; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D016516:CD4-CD8 Ratio; D019703:Calcineurin / Q000502:physiology; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D003208:Concanavalin A / Q000494:pharmacology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D005260:Female; D007106:Immune Sera / Q000494:pharmacology; D016130:Immunophenotyping; D007424:Intracellular Fluid / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1
D018106:CD28 Antigens; D017252:CD3 Complex; D065095:Calcineurin Inhibitors; D007106:Immune Sera; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003208:Concanavalin A; D019703:Calcineurin; D002118:Calcium