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.