CD8 co-receptor promotes susceptibility of CD8+ T cells to transforming growth factor-β (TGF-β)-mediated suppression

Andrew Zloza, Michael C. Jagoda, Gretchen E. Lyons, Michael C. Graves, Frederick J. Kohlhapp, Jeremy A. O'Sullivan, Andrew T. Lacek, Michael I. Nishimura, José A. Guevara-Patiño

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

CD8+ T cell function depends on a finely orchestrated balance of activation/suppression signals. While the stimulatory role of the CD8 co-receptor and pleiotropic capabilities of TGF-β have been studied individually, the influence of CD8 co-receptor on TGF-β function in CD8+ T cells is unknown. Here, we show that while CD8 enhances T cell activation, it also enhances susceptibility to TGF-β-mediated immune suppression. Using Jurkat cells expressing a full-length, truncated or no αβCD8 molecule, we demonstrate that cells expressing full-length αβCD8 were highly susceptible, αβCD8-truncated cells were partially susceptible, and CD8-deficient cells were completely resistant to suppression by TGF-β. Additionally, we determined that inhibition of Lck rendered mouse CD8+ T cells highly resistant to TGF-β suppression. Resistance was not associated with TGF-β receptor expression but did correlate with decreased Smad3 and increased Smad7 levels. These findings highlight a previously unrecognized third role for CD8 co-receptor which appears to prepare activated CD8+ T cells for response to TGF-β. Based on the important role which TGF-β-mediated suppression plays in tumor immunology, these findings unveil necessary considerations in formulation of CD8+ T cell-related cancer immunotherapy strategies.

Original languageEnglish (US)
Pages (from-to)291-297
Number of pages7
JournalCancer Immunology, Immunotherapy
Volume60
Issue number2
DOIs
StatePublished - Feb 2011

Funding

Acknowledgments The authors are grateful to the Flow Cytometry Facility and The Fitch Monoclonal Antibody Facility at The University of Chicago and the MUSC Center for Cellular Therapy for their invaluable support. The Center for Cellular Therapy is supported in part by the Clinical and Translational Science Award support grant (UL 1 RR029882) and the Hollings Cancer Center. This work was supported in part by the American Cancer Society (ACSLIB112496-RSG, to J. A. G.), American Cancer Society–Illinois Division (Young Investigator Award Grant #07-20, to J. A. G), the National Institutes of Health (R21CA127037-01A1 to J. A. G.), Cancer Research Foundation (Young Investigator Award, to J. A. G), National Institutes of Health (T32 Immunology Training Grant, The University of Chicago, AI07090 to A.Z. and AI00790 to F. J. K.), and the National Institutes of Health (R01CA104947, to M. I. N.). The authors have no financial conflicts of interest to disclose.

Keywords

  • CD8 T cells
  • CD8 co-receptor
  • Lck
  • SMADs
  • TGF-β
  • Tumor-induced suppression

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

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