TCR signaling intensity controls CD8+ T cell responsiveness to TGF-β. Issue 5 (7th July 2015)

• Record Type: Journal Article
• Authors: Arumugam, Vidhyalakshmi; Bluemn, Theresa; Wesley, Erin; Schmidt, Amanda M; Kambayashi, Taku; Malarkannan, Subramaniam; Riese, Matthew J
• Is Part Of: Journal of leukocyte biology. Volume 98:Issue 5(2015)
• Page Start: 703
• Page End: 712
• Publication Date: 2015-07-07
• Subjects: Diacylglycerol -- diacylglycerol kinase ζ -- Smad2; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1189/jlb.2HIMA1214-578R
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract : Enhancing TCR signal strength can attenuate TGFβ-mediated transcriptional changes and functions in CD8 + T cells, independent of changes to canonical TGFβ signaling. Abstract: DGK-ζ is a negative regulator of TCR signaling that causes degradation of the second messenger DAG, terminating DAG-mediated activation of Ras and PKCθ. Cytotoxic T cells deficient in DGK-ζ demonstrate enhanced effector functions in vitro and antitumor activity in vivo, perhaps because of insensitivity to inhibitory cytokines. We sought to determine whether the enhanced responsiveness of DGK-ζ-deficient T cells renders them insensitive to the inhibitory cytokine TGF-β and to determine how the loss of DGK-ζ facilitates this insensitivity. We identified decreased transcriptional and functional responses to TGF-β in CD8 + DGK-ζ −/− T cells but preserved TGF-β-mediated conversion of naϊve DGK-ζ −/− CD4 + T cells to a regulatory T cell phenotype. Decreased CD8 + T cell responsiveness to TGF-β did not result from impaired canonical TGF-β signal transduction, because similar levels of TGF-β-R and intracellular Smad components were identified in WT and DGK-ζ −/− CD8 + T cells, and TGF-β-mediated activation of Smad2 was unchanged. Instead, an enhanced TCR signal strength was responsible for TGF-β insensitivity, because (i) loss of DGK-ζ conferred resistance to TGF-β-mediated inhibition of Erk phosphorylation, (ii) TGF-β insensitivity could be recapitulated by exogenous addition of the DAG analog PMA, and (iii) TGF-β sensitivity could be observed in DGK-ζ-deficient T cells at limiting dilutions of TCR stimulation. These data indicate that enhanced TCR signal transduction in the absence of DGK-ζ makes T cells relatively insensitive to TGF-β, in a manner independent of Smads, a finding with practical implications in the development of immunotherapies that target TGF-β.