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Journal of Virology, May 2005, p. 5400-5413, Vol. 79, No. 9
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.9.5400-5413.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Highly Protective In Vivo Function of Cytomegalovirus IE1 Epitope-Specific Memory CD8 T Cells Purified by T-Cell Receptor-Based Cell Sorting

Marcus-Folker Pahl-Seibert,1 Markus Juelch,2,{dagger} Jürgen Podlech,1 Doris Thomas,1 Petra Deegen,1 Matthias J. Reddehase,1* and Rafaela Holtappels1

Institute for Virology,1 Tumor Vaccination Centre at the III. Medical Clinic, Johannes Gutenberg-University, Mainz, Germany2

Received 2 September 2004/ Accepted 23 December 2004

Reconstitution of antiviral CD8 T cells is essential for controlling cytomegalovirus (CMV) infection after bone marrow transplantation. Accordingly, polyclonal CD8 T cells derived from BALB/c mice infected with murine CMV protect immunocompromised adoptive transfer recipients against CMV disease. The protective population comprises CD8 T cells with T-cell receptors (TCRs) specific for defined and for as-yet-unknown viral epitopes, as well as a majority of nonprotective cells with unrelated specificities. Defined epitopes include IE1/m123 and m164, which are immunodominant in terms of the magnitude of the CD8 T-cell response, and a panel of subordinate epitopes (m04, m18, M45, M83, and M84). While cytolytic T-lymphocyte lines (CTLLs) were shown to be protective regardless of the immunodominance of the respective epitope, the individual contributions of in vivo resident epitope-specific CD8 T cells to the antiviral control awaited investigation. The IE1 peptide 168-YPHFMPTNL-176 is generated from the immediate-early protein 1 (IE1) (pp89/76) of murine CMV and is presented by the major histocompatibility complex class I (MHC-I) molecule Ld. To quantitate its contribution to the protective potential of a CD8-T memory (CD8-TM) cell population, IE1-TCR+ and IE1-TCR– CD8-TM cells were purified by epitope-specific cell sorting with IE1 peptide-loaded MHC-immunoglobulin G1 dimers as ligands of cognate TCRs. Of relevance for clinical approaches to an adoptive cellular immunotherapy, sorted IE1 epitope-specific CD8-TM cells were found to be exceedingly protective upon adoptive transfer. Compared with CTLLs specific for the same epitope and of comparable avidity and TCR ß-chain variable region (Vß)-defined polyclonality, sorted CD8-TM cells proved to be superior by more than 2 orders of magnitude.

* Corresponding author. Mailing address: Institute for Virology, Johannes Gutenberg-University, Hochhaus am Augustusplatz, 55101 Mainz, Germany. Phone: 49-6131-39-33650. Fax: 49-6131-39-35604. E-mail: Matthias.Reddehase{at}uni-mainz.de.

{dagger} Present address: THYMED GmbH, 55116 Mainz, Germany.

Journal of Virology, May 2005, p. 5400-5413, Vol. 79, No. 9
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.9.5400-5413.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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