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Journal of Virology, September 2009, p. 9068-9078, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.00141-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Upregulation of Interleukin 7 Receptor Alpha and Programmed Death 1 Marks an Epitope-Specific CD8+ T-Cell Response That Disappears following Primary Epstein-Barr Virus Infection{triangledown} ,{dagger}

Delphine Sauce,1,2 Martin Larsen,1 Rachel J. M. Abbott,1 Andrew D. Hislop,1 Alison M. Leese,1 Naeem Khan,1 Laura Papagno,2 Gordon J. Freeman,3 and Alan B. Rickinson1*

CRUK Institute for Cancer Studies and MRC Centre for Immune Regulation, University of Birmingham, Birmingham, United Kingdom,1 INSERM U543, Hôpital Pitié-Salpétrière, Université Pierre et Marie Curie 6, Paris, France,2 Department of Medical Oncology, Dana Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts3

Received 21 January 2009/ Accepted 29 June 2009

In immunocompetent individuals, the stability of the herpesvirus-host balance limits opportunities to study the disappearance of a virus-specific CD8+ T-cell response. However, we noticed that in HLA-A*0201-positive infectious mononucleosis (IM) patients undergoing primary Epstein-Barr virus (EBV) infection, the initial CD8 response targets three EBV lytic antigen-derived epitopes, YVLDHLIVV (YVL), GLCTLVAML (GLC), and TLDYKPLSV (TLD), but only the YVL and GLC reactivities persist long-term; the TLD response disappears within 10 to 27 months. While present, TLD-specific cells remained largely indistinguishable from YVL and GLC reactivities in many phenotypic and functional respects but showed unique temporal changes in two markers of T-cell fate, interleukin 7 receptor alpha (IL-7R{alpha}; CD127) and programmed death 1 (PD-1). Thus, following the antigen-driven downregulation of IL-7R{alpha} seen on all populations in acute IM, in every case, the TLD-specific population recovered expression unusually quickly post-IM. As well, in four of six patients studied, TLD-specific cells showed very strong PD-1 upregulation in the last blood sample obtained before the cells’ disappearance. Our data suggest that the disappearance of this individual epitope reactivity from an otherwise stable EBV-specific response (i) reflects a selective loss of cognate antigen restimulation (rather than of IL-7-dependent signals) and (ii) is immediately preceded, and perhaps mediated, by PD-1 upregulation to unprecedented levels.

* Corresponding author. Mailing address: CRUK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom. Phone: 44-121-414-4492. Fax: 44-121-414-4486. E-mail: A.B.Rickinson{at}bham.ac.uk

{triangledown} Published ahead of print on 15 July 2009.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, September 2009, p. 9068-9078, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.00141-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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