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

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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.

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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.

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Authors and Affiliations

  1. Department of Surgery, Committee on Immunology, The University of Chicago, Surgery Brain Research Building, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA

    Andrew Zloza, Michael C. Jagoda, Gretchen E. Lyons, Frederick J. Kohlhapp, Jeremy A. O’Sullivan, Andrew T. Lacek & José A. Guevara-Patiño

  2. Division of General Surgery, Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA

    Michael C. Graves & Michael I. Nishimura

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  1. Andrew Zloza
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  2. Michael C. Jagoda
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  3. Gretchen E. Lyons
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  9. José A. Guevara-Patiño
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Correspondence to José A. Guevara-Patiño.

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262_2010_962_MOESM1_ESM.tif

Supplemental Fig. 1 Expression of CD8 co-receptor on Jurkat cells and relative percent suppression of IL-2 production after Lck inhibitor treatment. A, Expression of αβCD8 on untreated respective Jurkat cells was determined by flow cytometric analysis. Gray histograms represent isotype staining. B, Relative % suppression of IL-2 production by treated Jurkat cells (as described in Fig. 1B) ± Lck inhibitor (50 ng/ml). ** denotes P < 0.01. Figures represent one set of experiments done in triplicate and repeated at least two additional times with similar results. (TIFF 473 kb)

262_2010_962_MOESM2_ESM.tif

Supplemental Fig. 2 CD8-Lck impacts the susceptibility of OT-I mouse CD8+ T cells to TGF-β-mediated suppression A, Cumulative figure of mean granzyme B production by mouse OT-I CD8+ T cells after 4-hour culture with OVA257–264 peptide (1 μg/ml) ± 50 ng/ml TGF-β ± Lck inhibitor (50 ng/ml or 1 μg/ml, as indicated). B, Graphical representation of relative % suppression by TGF-β from data in A. C, Smad3 levels after 30-minute coculture (as described in A). D, Smad7 levels after coculture (as described in C). E, Expression of Lck by OT-I CD8+ T cells after culture as described in A. F, Expression of TGF-β-RI by OT-I mouse CD8+ T cells after 30-minute culture as described in A. G, Expression of TGF-β-RII as described in F. * denotes P < 0.05, ** P < 0.01, *** P < 0.001. Dashed line represents background staining. Figures represent one set of experiments done in triplicate and repeated at least two additional times with similar results. (TIFF 115 kb)

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Zloza, A., Jagoda, M.C., Lyons, G.E. et al. CD8 Co-receptor promotes susceptibility of CD8+ T cells to transforming growth factor-β (TGF-β)-mediated suppression. Cancer Immunol Immunother 60, 291–297 (2011). https://doi.org/10.1007/s00262-010-0962-6

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