Skip to main content

Advertisement

SpringerLink
Log in

Relationship between CD8-dependent antigen recognition, T cell functional avidity, and tumor cell recognition

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Effective immunotherapy using T cell receptor (TCR) gene-modified T cells requires an understanding of the relationship between TCR affinity and functional avidity of T cells. In this study, we evaluate the relative affinity of two TCRs isolated from HLA-A2-restricted, gp100-reactive T cell clones with extremely high functional avidity. Furthermore, one of these T cell clones, was CD4−CD8− indicating that antigen recognition by this clone was CD8 independent. However, when these TCRs were expressed in CD8− Jurkat cells, the resulting Jurkat cells recognized gp100:209–217 peptide loaded T2 cells and had high functional avidity, but could not recognize HLA-A2+ melanoma cells expressing gp100. Tumor cell recognition by Jurkat cells expressing these TCRs could not be induced by exogenously loading the tumor cells with the native gp100:209–217 peptide. These results indicate that functional avidity of a T cell does not necessarily correlate with TCR affinity and CD8-independent antigen recognition by a T cell does not always mean its TCR will transfer CD8-independence to other effector cells. The implications of these findings are that T cells can modulate their functional avidity independent of the affinity of their TCRs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Boon T, Coulie PG, Van den Eynde B (1997) Tumor antigens recognized by T cells. Immunol Today 18(6):267–268

    Article  PubMed  CAS  Google Scholar 

  2. Rosenberg SA (1999) A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity 10(3):281–287

    Article  PubMed  CAS  Google Scholar 

  3. Mizoguchi H, O’Shea JJ, Longo DL, Loeffler CM, McVicar DW, Ochoa AC (1992) Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science 258(5089):1795–1798

    Article  PubMed  CAS  Google Scholar 

  4. Finke JH, Zea AH, Stanley J, Longo DL, Mizoguchi H, Tubbs RR, Wiltrout RH, O’Shea JJ, Kudoh S, Klein E, Bukowski RM, Ochoa AC (1993) Loss of T-cell receptor zeta chain and p56lck in T-cells infiltrating human renal cell carcinoma. Cancer Res 53(23):5613–5616

    PubMed  CAS  Google Scholar 

  5. Alexander-Miller MA, Leggatt GR, Berzofsky JA (1996) Selective expansion of high- or low-avidity cytotoxic T lymphocytes and efficacy for adoptive immunotherapy. Proc Natl Acad Sci 93(9):4102–4107

    Article  PubMed  CAS  Google Scholar 

  6. Zeh HJ, Perry-Lalley D, Dudley ME, Rosenberg SA, Yang JC (1999) High avidity CTLs for two self-antigens demonstrate superior in vitro and in vivo antitumor efficacy. J Immunol 162(2):989–994

    PubMed  CAS  Google Scholar 

  7. Dudley ME, Nishimura MI, Holt AK, Rosenberg SA (1999) Antitumor immunization with a minimal peptide epitope (G9–209–2 M) leads to a functionally heterogeneous CTL response. J Immunother 22(4):288–298

    Article  PubMed  CAS  Google Scholar 

  8. Clay TM, Custer MC, Sachs J, Hwu P, Rosenberg SA, Nishimura MI (1999) Efficient transfer of a tumor antigen-reactive TCR to human peripheral blood lymphocytes confers anti-tumor reactivity. J Immunol 163(1):507–513

    PubMed  CAS  Google Scholar 

  9. Duval L, Schmidt H, Kaltoft K, Fode K, Jensen JJ, Sorensen SM, Nishimura MI, von der Maase H (2006) Adoptive transfer of allogeneic cytotoxic T lymphocytes equipped with a HLA-A2 restricted MART-1 T-cell receptor: a phase I trial in metastatic melanoma. Clin Cancer Res 12(4):1229–1236

    Article  PubMed  CAS  Google Scholar 

  10. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, Rosenberg SA (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314(5796):126–129

    Article  PubMed  CAS  Google Scholar 

  11. Roszkowski JJ, Yu DC, Rubinstein MP, McKee MD, Cole DJ, Nishimura MI (2003) CD8 independent tumor cell recognition is a property of the T cell receptor and not the T cell. J Immunol 170(5):2582–2589

    PubMed  CAS  Google Scholar 

  12. Roszkowski JJ, Lyons GE, Kast WM, Yee C, Van Besien K, Nishimura MI (2005) Simultaneous generation of CD8+ and CD4+ melanoma reactive T cells by retroviral mediated TCR gene transfer. Cancer Res 65(4):1570–1576

    Article  PubMed  CAS  Google Scholar 

  13. Callender GG, Rosen HR, Roszkowski JJ, Lyons GE, Li M, Moore TV, Brasic N, McKee MD, Nishimura MI (2006) Identification of a CD8-independent Hepatitis C virus-specific T cell receptor that does not require CD8 for target cell recognition. Hepatology 43(5):973–981

    Article  PubMed  CAS  Google Scholar 

  14. Topalian SL, Solomon D, Rosenberg SA (1989) Tumor-specific cytolysis by lymphocytes infiltrating human melanomas. J Immunol 142(10):3714–3725

    PubMed  CAS  Google Scholar 

  15. Nishimura MI, Kawakami Y, Charmley P, O’Neil B, Shilyansky J, Yannelli JR, Rosenberg SA, Hood L (1994) T-cell receptor repertoire in tumor-infiltrating lymphocytes. Analysis of melanoma-specific long-term lines. J Immunother 16(2):85–94

    Article  CAS  Google Scholar 

  16. Shilyansky J, Nishimura MI, Yannelli JR, Kawakami Y, Jacknin LS, Charmley P, Rosenberg SA (1994) T-cell receptor usage by melanoma-specific clonal and highly oligoclonal tumor-infiltrating lymphocyte lines. Proc Natl Acad Sci 91(7):2829–2833

    Article  PubMed  CAS  Google Scholar 

  17. Deveraux J, Haeberli P, Smithies O (1984) A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res 12(1):387–395

    Article  Google Scholar 

  18. McKee MD, Roszkowski JJ, Nishimura MI (2005) T cell avidity and tumor recognition: implications and therapeutic strategies. J Transl Med 3:35

    Article  PubMed  CAS  Google Scholar 

  19. Kedzierska K, La Gruta NL, Davenport MP, Turner SJ, Doherty PC (2005) Contribution of T cell receptor affinity to overall avidity for virus-specific CD8+ T cell responses. Proc Natl Acad Sci 102(32):11432–11437

    Article  PubMed  CAS  Google Scholar 

  20. Trautmann L, Rimbert M, Echasserieau K, Saulquin X, Neveu B, Dechanet J, Cerundolo V, Bonneville M (2005) Selection of T cell clones expressing high-affinity public TCRs within Human cytomegalovirus-specific CD8 T cell responses. J Immunol 175(9):6123–6132

    PubMed  CAS  Google Scholar 

  21. Iero M, Squarcina P, Romero P, Guillaume P, Scarselli E, Cerino R, Carrabba M, Toutirais O, Parmiani G, Rivoltini L (2007) Low TCR avidity and lack of tumor cell recognition in CD8(+) T cells primed with the CEA-analogue CAP1–6D peptide. Cancer Immunol Immunother 56(12):1979–1991

    Article  PubMed  CAS  Google Scholar 

  22. Kim M, Moon HB, Kim K, Lee KY (2006) Antigen dose governs the shaping of CTL repertoires in vitro and in vivo. Int Immunol 18(3):435–444

    Article  PubMed  CAS  Google Scholar 

  23. Dudley ME, Wunderlich J, Nishimura MI, Yu D, Yang JC, Topalian SL, Schwartzentruber DJ, Hwu P, Marincola FM, Sherry R, Leitman SF, Rosenberg SA (2001) Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma. J Immunother 24(4):363–373

    Article  PubMed  CAS  Google Scholar 

  24. Koop BF, Rowen L, Wang K, Kuo CL, Seto D, Lenstra JA, Howard S, Shan W, Deshpande P, Hood L (1994) The human T-cell receptor TCRAC/TCRDC (C alpha/C delta) region: organization, sequence, and evolution of 97.6 kb of DNA. Genomics 19(3):478–493

    Article  PubMed  CAS  Google Scholar 

  25. Cole DJ, Weil DP, Shilyansky J, Custer M, Kawakami Y, Rosenberg SA, Nishimura MI (1995) Characterization of the functional specificity of a cloned T-cell receptor heterodimer recognizing the MART-1 melanoma antigen. Cancer Res 55(4):748–752

    PubMed  CAS  Google Scholar 

  26. Parkhurst MR, Salgaller ML, Southwood S, Robbins PF, Sette A, Rosenberg SA, Kawakami Y (1996) Improved induction of melanoma-reactive CTL with peptides from the melanoma antigen gp100 modified at HLA-A*0201-binding residues. J Immunol 157(6):2539–2548

    PubMed  CAS  Google Scholar 

  27. Seliger B (2008) Molecular mechanisms of MHC class I abnormalities and APM components in human tumors. Cancer Immunol Immunother. [Epub ahead of print]

  28. Seliger B, Ritz U, Ferrone S (2006) Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation. Int J Cancer 118(1):129–138

    Article  PubMed  CAS  Google Scholar 

  29. Ortmann B, Copeman J, Lehner PJ, Sadasivan B, Herberg JA, Grandea AG, Riddell SR, Tampé R, Spies T, Trowsdale J, Cresswell P (1997) A critical role for tapasin in the assembly and function of multimeric MHC class I-TAP complexes. Science 277(5330):1306–1309

    Article  PubMed  CAS  Google Scholar 

  30. Nishimura MI, Avichezer D, Custer MC, Lee CS, Chen C, Parkhurst MR, Diamond RA, Robbins PF, Schwartzentruber DJ, Rosenberg SA (1999) MHC class I-restricted recognition of a melanoma antigen by a human CD4+ tumor infiltrating lymphocyte. Cancer Res 59(24):6230–6238

    PubMed  CAS  Google Scholar 

  31. Theobald M, Biggs J, Dittmer D, Levine AJ, Sherman LA (1995) Targeting p53 as a general tumor antigen. Proc Natl Acad Sci 92(26):11993–11997

    Article  PubMed  CAS  Google Scholar 

  32. Kuball J, Schmitz FW, Voss RH, Ferreira EA, Engel R, Guillaume P, Strand S, Romero P, Huber C, Sherman LA, Theobald M (2005) Cooperation of human tumor-reactive CD4+ and CD8+ T cells after redirection of their specificity by a high-affinity p53A2.1-specific TCR. Immunity 22(1):117–129

    Article  PubMed  CAS  Google Scholar 

  33. Santomasso BD, Roberts WK, Thomas A, Williams T, Blachere NE, Dudley ME, Houghton AN, Posner JB, Darnell RB (2007) A T-cell receptor associated with naturally occurring human tumor immunity. Proc Natl Acad Sci 104(48):19073–19078

    Article  PubMed  CAS  Google Scholar 

  34. van den Boorn JG, Le Poole IC, Luiten RM (2006) T-cell avidity and tuning: the flexible connection between tolerance and autoimmunity. Int Rev Immunol 25(3–4):235–258

    Article  PubMed  CAS  Google Scholar 

  35. Jenkins MK, Schwartz RH (1987) Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med 165(2):302–319

    Article  PubMed  CAS  Google Scholar 

  36. Beverly B, Kang SM, Lenardo MJ, Schwartz RH (1992) Reversal of in vitro T cell clonal anergy by IL-2 stimulation. Int Immunol 4(6):661–671

    Article  PubMed  CAS  Google Scholar 

  37. Rosenberg SA, Spiess P, Lafreniere R (1986) A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 233(4770):1318–1321

    Article  PubMed  CAS  Google Scholar 

  38. Aebersold P, Hyatt C, Johnson S, Hines K, Korcak L, Sanders M, Lotze M, Topalian S, Yang J, Rosenberg SA (1991) Lysis of autologous melanoma cells by tumor-infiltrating lymphocytes: association with clinical response. J Natl Cancer Inst 83(13):932–937

    Article  PubMed  CAS  Google Scholar 

  39. Alexander-Miller MA, Leggatt GR, Sarin A, Berzofsky JA (1996) Role of antigen, CD8, and cytotoxic T lymphocyte (CTL) avidity in high dose antigen induction of apoptosis of effector CTL. J Exp Med 184(2):485–492

    Article  PubMed  CAS  Google Scholar 

  40. Cawthon AG, Lu H, Alexander-Miller MA (2001) Peptide requirement for CTL activation reflects the sensitivity to CD3 engagement: correlation with CD8alphabeta versus CD8alphaalpha expression. J Immunol 167(5):2577–2584

    PubMed  CAS  Google Scholar 

  41. Cawthon AG, Alexander-Miller MA (2002) Optimal colocalization of TCR and CD8 as a novel mechanism for the control of functional avidity. J Immunol 169(7):3492–3498

    PubMed  CAS  Google Scholar 

  42. Lyons GE, Moore T, Brasic N, Li M, Roszkowski JJ, Nishimura MI (2006) Influence of human CD8 on antigen recognition by T-cell receptor-transduced cells. Cancer Res 66(23):11455–11461

    Article  PubMed  CAS  Google Scholar 

  43. Lyons GE, Roszkowski JJ, Man S, Yee C, Kast WM, Nishimura MI (2006) T-cell receptor tetramer binding or the lack there of does not necessitate antigen reactivity in T cell receptor transduced T-cells. Cancer Immunol Immunother 55(9):1142–1150

    Article  PubMed  CAS  Google Scholar 

  44. Gil D, Schrum AG, Alarcón B, Palmer E (2005) T cell receptor engagement by peptide-MHC ligands induces a conformational change in the CD3 complex of thymocytes. J Exp Med 201(4):517–522

    Article  PubMed  CAS  Google Scholar 

  45. Schamel WW, Risueño RM, Minguet S, Ortíz AR, Alarcón B (2006) A conformation- and avidity-based proofreading mechanism for the TCR-CD3 complex. Trends Immunol 27(4):176–182

    Article  PubMed  CAS  Google Scholar 

  46. Minguet S, Swamy M, Alarcón B, Luescher IF, Schamel WW (2007) Full activation of the T cell receptor requires both clustering and conformational changes at CD3. Immunity 26(1):43–54

    Article  PubMed  CAS  Google Scholar 

  47. Petersen TR, Gülland S, Bettelli E, Kuchroo V, Palmer E, Bäckström BT (2004) A chimeric T cell receptor with super-signaling properties. Int Immunol 16(7):889–894

    Article  PubMed  CAS  Google Scholar 

  48. Cohen CJ, Zhao Y, Zheng Z, Rosenberg SA, Morgan RA (2006) Enhanced antitumor activity of murine-human hybrid T-cell receptor (TCR) in human lymphocytes is associated with improved pairing and TCR/CD3 stability. Cancer Res 66(17):8878–8886

    Article  PubMed  CAS  Google Scholar 

  49. Kuball J, Dossett ML, Wolfl M, Ho WY, Voss RH, Fowler C, Greenberg PD (2007) Facilitating matched pairing and expression of TCR chains introduced into human T cells. Blood 109(6):2331–2338

    Article  PubMed  CAS  Google Scholar 

  50. Cohen CJ, Li YF, El-Gamil M, Robbins PF, Rosenberg SA, Morgan RA (2007) Enhanced antitumor activity of T cells engineered to express T-cell receptors with a second disulfide bond. Cancer Res 67(8):3898–3903

    Article  PubMed  CAS  Google Scholar 

  51. Voss RH, Willemsen RA, Kuball J, Grabowski M, Engel R, Intan RS, Guillaume P, Romero P, Huber C, Theobald M (2008) Molecular design of the Calphabeta interface favors specific pairing of introduced TCRalphabeta in human T cells. J Immunol 180(1):391–401

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors wish to acknowledge support from the Walter A. Richter Cancer Research Chair held by WKM. The authors also wish to acknowledge the University of Chicago Flow Cytometry Core. This work was supported by NIH grants CA90873, CA102280, 104947 (awarded to MIN), CA 97296 (awarded to WMK) and CA109536 (awarded to ICLP).

Author information

Authors and Affiliations

  1. Department of Surgery, The University of Chicago, Chicago, IL, 60637, USA

    Tamson V. Moore, Gretchen E. Lyons, Natasha Brasic, Jeffrey J. Roszkowski & Michael I. Nishimura

  2. Department of Internal Medicine 5, Hematology/Oncology, University of Erlangen, 91054, Erlangen, Germany

    Simon Voelkl & Andreas Mackensen

  3. Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA

    W. Martin Kast

  4. Departments of Molecular Microbiology & Immunology and Obstetrics & Gynecology, University of Southern California, Los Angeles, CA, 90033, USA

    W. Martin Kast

  5. Departments of Pathology and Microbiology & Immunology, Loyola University Medical Center, Maywood, IL, 60153, USA

    I. Caroline Le Poole

  6. Department of Surgery, Medical University of South Carolina, 86 Jonathan Lucas Street, Suite 512H, P.O. Box 250613, Charleston, USA

    Michael I. Nishimura

Authors
  1. Tamson V. Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gretchen E. Lyons
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Natasha Brasic
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeffrey J. Roszkowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Simon Voelkl
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andreas Mackensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W. Martin Kast
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. I. Caroline Le Poole
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michael I. Nishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael I. Nishimura.

Additional information

Companion Paper: “Characterization of MHC class-I restricted TCRαβ+ CD4− CD8− double negative T cells recognizing the gp100 antigen from a melanoma patient after gp100 vaccination” by Simon Voelkl, Tamson V. Moore, Michael Rehli, Michael I. Nishimura, Andreas Mackensen, and Karin Fischer. doi:10.1007/s00262-008-0593-3.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moore, T.V., Lyons, G.E., Brasic, N. et al. Relationship between CD8-dependent antigen recognition, T cell functional avidity, and tumor cell recognition. Cancer Immunol Immunother 58, 719–728 (2009). https://doi.org/10.1007/s00262-008-0594-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-008-0594-2

Keywords

Search

Navigation