Mechanistic studies of transforming growth factor-beta inhibition of IL-2-dependent activation of CD3- large granular lymphocyte functions. Regulation of IL-2R beta (p75) signal transduction.
CD3- large granular lymphocyte (LGL) express constitutive levels of functional IL-2R beta. TGF-beta inhibited several IL-2R beta-mediated events in LGL, including IL-2-induced NK and lymphokine-activating factor activities, IFN-gamma gene expression and secretion, and IL-2R alpha expression. TGF-beta inhibited these IL-2-induced LGL functions in a dose-dependent and reversible manner. By contrast, TGF-beta had little effect on LGL IL-2R beta expression and TGF-beta receptors were not induced by IL-2. Studies were performed to examine binding and internalization of radiolabeled IL-2. These experiments demonstrated that the rapid binding and internalization of [125I]IL-2 was not altered in CD3- LGL pretreated with TGF-beta. These internalization studies indicated that the TGF-beta inhibition represented postreceptor-binding events in NK cells. Further studies were initiated to examine signaling events in CD3- LGL. When IL-2-induced tyrosine phosphorylation events were examined, significant inhibition was seen of selected phosphoproteins in TGF-beta-pretreated cells. In addition, the ability of TGF-beta to also inhibit IL-2 induction of LGL IL-2R alpha and IFN-gamma mRNA expression was consistent with the hypothesis that posttranscriptional mechanisms were unlikely to be affected by TGF-beta. Collectively, these data indicated that TGF-beta inhibited IL-2-induced CD3- LGL functions and suggested that TGF-beta inhibition occurs either at the level of specific tyrosine phosphorylation and/or IL-2-induced transcriptional control factors.
Ortaldo
J R
JR
Laboratory of Experimental Immunology, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702-1201.
Mason
A T
AT
O'Shea
J J
JJ
Smyth
M J
MJ
Falk
L A
LA
Kennedy
I C
IC
Longo
D L
DL
Ruscetti
F W
FW
D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis*; D017252:CD3 Complex; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D011948:Receptors, Antigen, T-Cell / Q000032:analysis*; D011956:Receptors, Cell Surface / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000032:analysis* / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D007376:Interleukin-2; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; D015375:Receptors, Interleukin-2; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D014443:Tyrosine