Distinct effects of TGF-beta 1 on CD4+ and CD8+ T cell survival, division, and IL-2 production: a role for T cell intrinsic Smad3.
TGF-beta1 is critical for maintaining T cell homeostasis. Smad3 has been implicated in this regulatory process, yet the cellular targets and molecular details remain poorly understood. In this study, we report that TGF-beta1 impairs the entry of CD4+ and CD8+ T cells into the cell cycle as well as their progression through subsequent rounds of division, and show that Smad3 is essential for TGF-beta1 to inhibit TCR-induced division of only CD4+ and not CD8+ T cells. Both CD8+ and CD4+ T cells from Smad3-/- mice were refractory to TGF-beta1-induced inhibition of IL-2 production, thus demonstrating that not all CD8+ T cell responses to TGF-beta1 are Smad3 independent. These TGF-beta1 effects were all T cell intrinsic, as they were reproduced in purified CD4+ and CD8+ T cells. Finally, we found that Smad3 was critical for the survival of CD8+, but not CD4+ T cells following activation ex vivo. The TCR-induced death of Smad3-/- CD8+ T cells was not dependent upon TNF-alpha production. Exogenous TGF-beta1 partially rescued the CD8+ T cells by signaling through a Smad3-independent pathway. TGF-beta1 also enhanced survival of TCR-stimulated CD4+CD44high T cells in a Smad3-independent manner. Collectively, these findings firmly establish for the first time that TGF-beta1 discriminately regulates CD4+ and CD8+ T cell expansion by signaling through distinct intracellular pathways.
McKarns
Susan C
SC
Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. smckarns@niaid.nih.gov
Schwartz
Ronald H
RH
D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006131:Growth Inhibitors / Q000502:physiology; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051900:Smad3 Protein; D015534:Trans-Activators / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology
D000276:Adjuvants, Immunologic; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D018960:Hyaluronan Receptors; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha