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Modulation of cord blood CD8+ T-cell effector differentiation by TGF-beta1 and 4-1BB costimulation.
Blood. 2005 Jan 01; 105(1):274-81.Blood

Abstract

Transforming growth factor-beta1 (TGF-beta1), an immunosuppressive cytokine, inhibits cytotoxic T cell (CTL) immune responses. In contrast, 4-1BB (CD137), a costimulatory molecule in the tumor necrosis factor (TNF) receptor family, amplifies CTL-mediated antitumor immune responses. We investigated whether TGF-beta1 responses could be reversed by 4-1BB costimulation during in vitro differentiation of naive CD8+ T cells into effector CTL cells. TGF-beta1 potently suppressed CTL differentiation of human cord blood naive CD8+ T cells as determined by reduced induction of characteristic phenotypes of effector cells and cytotoxic activity. TGF-beta1-mediated suppression of CTL differentiation was abrogated by 4-1BB costimulation but not by CD28 or another member in the TNF receptor family, CD30. 4-1BB costimulation suppressed Smad2 phosphorylation induced by TGF-beta1, suggesting that 4-1BB effects were at the level of TGF-beta1 signaling. 4-1BB effects on the TGF-beta1-mediated suppression were enhanced by interleukin 12 (IL-12) but counteracted by IL-4; 4-1BB expression was up- or down-regulated, respectively, by IL-12 and IL-4. IL-4 was more dominant than IL-12 when both cytokines were present during 4-1BB costimulation in the presence of TGF-beta1. This indicates critical roles for IL-4 and IL-12 in regulating 4-1BB effects on TGF-beta1-mediated suppression.

Authors+Show Affiliations

Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis 46202-5181, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15353478

Citation

Kim, Young-June, et al. "Modulation of Cord Blood CD8+ T-cell Effector Differentiation By TGF-beta1 and 4-1BB Costimulation." Blood, vol. 105, no. 1, 2005, pp. 274-81.
Kim YJ, Stringfield TM, Chen Y, et al. Modulation of cord blood CD8+ T-cell effector differentiation by TGF-beta1 and 4-1BB costimulation. Blood. 2005;105(1):274-81.
Kim, Y. J., Stringfield, T. M., Chen, Y., & Broxmeyer, H. E. (2005). Modulation of cord blood CD8+ T-cell effector differentiation by TGF-beta1 and 4-1BB costimulation. Blood, 105(1), 274-81.
Kim YJ, et al. Modulation of Cord Blood CD8+ T-cell Effector Differentiation By TGF-beta1 and 4-1BB Costimulation. Blood. 2005 Jan 1;105(1):274-81. PubMed PMID: 15353478.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modulation of cord blood CD8+ T-cell effector differentiation by TGF-beta1 and 4-1BB costimulation. AU - Kim,Young-June, AU - Stringfield,Teresa M, AU - Chen,Yan, AU - Broxmeyer,Hal E, Y1 - 2004/09/07/ PY - 2004/9/9/pubmed PY - 2005/2/11/medline PY - 2004/9/9/entrez SP - 274 EP - 81 JF - Blood JO - Blood VL - 105 IS - 1 N2 - Transforming growth factor-beta1 (TGF-beta1), an immunosuppressive cytokine, inhibits cytotoxic T cell (CTL) immune responses. In contrast, 4-1BB (CD137), a costimulatory molecule in the tumor necrosis factor (TNF) receptor family, amplifies CTL-mediated antitumor immune responses. We investigated whether TGF-beta1 responses could be reversed by 4-1BB costimulation during in vitro differentiation of naive CD8+ T cells into effector CTL cells. TGF-beta1 potently suppressed CTL differentiation of human cord blood naive CD8+ T cells as determined by reduced induction of characteristic phenotypes of effector cells and cytotoxic activity. TGF-beta1-mediated suppression of CTL differentiation was abrogated by 4-1BB costimulation but not by CD28 or another member in the TNF receptor family, CD30. 4-1BB costimulation suppressed Smad2 phosphorylation induced by TGF-beta1, suggesting that 4-1BB effects were at the level of TGF-beta1 signaling. 4-1BB effects on the TGF-beta1-mediated suppression were enhanced by interleukin 12 (IL-12) but counteracted by IL-4; 4-1BB expression was up- or down-regulated, respectively, by IL-12 and IL-4. IL-4 was more dominant than IL-12 when both cytokines were present during 4-1BB costimulation in the presence of TGF-beta1. This indicates critical roles for IL-4 and IL-12 in regulating 4-1BB effects on TGF-beta1-mediated suppression. SN - 0006-4971 UR - https://www.unboundmedicine.com/medline/citation/15353478/Modulation_of_cord_blood_CD8+_T_cell_effector_differentiation_by_TGF_beta1_and_4_1BB_costimulation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/2003-12-4343 DB - PRIME DP - Unbound Medicine ER -