The Journal of Immunology, Vol 146, Issue 11 3791-3798, Copyright © 1991 by American Association of Immunologists

ARTICLES

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

JR Ortaldo, AT Mason, JJ O'Shea, MJ Smyth, LA Falk, IC Kennedy, DL Longo and FW Ruscetti
Laboratory of Experimental Immunology, National Cancer Institute- Frederick Cancer Research and Development Center, MD 21702-1201.

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.

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