Low dose TGF-beta attenuates IL-12 responsiveness in murine Th cells.
Expression of IL-12Rs is one important checkpoint for Th1 development. BALB/c DO11.10 CD4+ T cells stimulated by Ag in neutral conditions lose expression of the IL-12R beta 2 subunit and become unresponsive to IL-12. In contrast, B10.D2 or F1 (BALB/c x B10.D2) DO11.10 CD4+ T cells maintain IL-12R beta 2 expression when stimulated similarly. Here we show that the loss of IL-12 responsiveness by BALB/c T cells involves the action of endogenous TGF-beta. BALB/c T cells stimulated in the presence of anti-TGF-beta specifically maintain IL-12 responsiveness, express IL-12R beta 2 mRNA, and can stimulate nitric oxide production in peritoneal exudate cells. Low concentrations of TGF-beta added exogenously during primary activation of B10.D2 or F1 T cells significantly inhibit their development of IL-12 responsiveness. These effects of anti-TGF-beta are dependent on endogenous IFN-gamma and are inhibited by exogenously added IL-4. Thus, at least one effect of TGF-beta on Th1/Th2 development may be the attenuation of IL-12R beta 2 expression.
Dartmouth Medical School-DHMC, Department of Pathology, Lebanon, NH 03756, USA.
J D
JD
Gorham
M L
ML
Güler
D
D
Fenoglio
U
U
Gubler
K M
KM
Murphy
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D018664:Interleukin-12 / Q000378:metabolism / Q000502:physiology*; D008198:Lymph Nodes; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053707:Receptors, Interleukin-12; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D016212:Transforming Growth Factor beta; D018664:Interleukin-12