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1 to Suppress IL-2 Production and TCR-Induced Proliferation, but Not IL-2-Induced Proliferation1
* Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824; and
Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
Transforming growth factor-
1 is essential to maintain T cell homeostasis, as illustrated by multiorgan inflammation in mice deficient in TGF-1 signaling. Despite the physiological importance, the mechanisms that TGF-1 uses to regulate T cell expansion remain poorly understood. TGF-1 signals through transmembrane receptor serine/threonine kinases to activate multiple intracellular effector molecules, including the cytosolic signaling transducers of the Smad protein family. We used Smad3-/- mice to investigate a role for Smad3 in IL-2 production and proliferation in T cells. Targeted disruption of Smad3 abrogated TGF-1-mediated inhibition of anti-CD3 plus anti-CD28-induced steady state IL-2 mRNA and IL-2 protein production. CFSE labeling demonstrated that TGF-1 inhibited entry of wild-type anti-CD3 plus anti-CD28-stimulated cells into cycle cell, and this inhibition was greatly attenuated in Smad3-/- T cells. In contrast, disruption of Smad3 did not affect TGF-1-mediated inhibition of IL-2-induced proliferation. These results demonstrate that TGF-1 signals through Smad3-dependent and -independent pathways to inhibit T cell proliferation. The inability of TGF-1 to inhibit TCR-induced proliferation of Smad3-/- T cells suggests that IL-2 is not the primary stimulus driving expansion of anti-CD3 plus anti-CD28-stimulated T cells. Thus, we establish that TGF-1 signals through multiple pathways to suppress T cell proliferation.
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