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Journal of Virology, April 2009, p. 2862-2871, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.02528-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Distinct Profiles of Cytotoxic Granules in Memory CD8 T Cells Correlate with Function, Differentiation Stage, and Antigen Exposure ^,

Alexandre Harari,^1, Felicitas Bellutti Enders,^1, Cristina Cellerai,¹ Pierre-Alexandre Bart,¹ and Giuseppe Pantaleo^1,2*

Laboratory of AIDS Immunopathogenesis, Division of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne,¹ Swiss Vaccine Research Institute, Lausanne, Switzerland²

Received 9 December 2008/ Accepted 16 January 2009

Cytotoxic CD8 T cells exert their antiviral and antitumor activity primarily through the secretion of cytotoxic granules. Degranulation activity and cytotoxic granules (perforin plus granzymes) generally define CD8 T cells with cytotoxic function. In this study, we have investigated the expression of granzyme K (GrmK) in comparison to that of GrmA, GrmB, and perforin. The expression of the cytotoxic granules was assessed in virus-specific CD8 T cells specific to influenza virus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), or human immunodeficiency virus type 1 (HIV-1). We observed a dichotomy between GrmK and perforin expression in virus-specific CD8 T cells. The profile in influenza virus-specific CD8 T cells was perforin^– GrmB^– GrmA^+/– GrmK⁺; in CMV-specific cells, it was perforin⁺ GrmB⁺ GrmA⁺ GrmK^–/+; and in EBV- and HIV-1-specific cells, it was perforin^–/+ GrmB⁺ GrmA⁺ GrmK⁺. On the basis of the delineation of memory and effector CD8 T cells with CD45RA and CD127, the GrmK⁺ profile was associated with early-stage memory CD8 T-cell differentiation, the perforin⁺ GrmB⁺ GrmA⁺ profile with advanced-stage differentiation, and the GrmB⁺ GrmA⁺ Grmk⁺ profile with intermediate-stage differentiation. Furthermore, perforin and GrmB but not GrmA and GrmK correlated with cytotoxic activity. Finally, changes in antigen exposure in vitro and in vivo during primary HIV-1 infection and vaccination modulated cytotoxic granule profiles. These results advance our understanding of the relationship between distinct profiles of cytotoxic granules in memory CD8 T cells and function, differentiation stage, and antigen exposure.

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* Corresponding author. Mailing address: Laboratory of AIDS Immunopathogenesis, Division of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland. Phone: 41-21-314-10-71. Fax: 41-21-314-10-70. E-mail: giuseppe.pantaleo{at}chuv.ch

Published ahead of print on 28 January 2009.

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

A.H. and F.B.E. contributed equally to this study.

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Journal of Virology, April 2009, p. 2862-2871, Vol. 83, No. 7
0022-538X/09/$08.00+0     doi:10.1128/JVI.02528-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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