Highly protective in vivo function of cytomegalovirus IE1 epitope-specific memory CD8 T cells purified by T-cell receptor-based cell sorting

MF Pahl-Seibert, M Juelch, J Podlech… - Journal of …, 2005 - Am Soc Microbiol
MF Pahl-Seibert, M Juelch, J Podlech, D Thomas, P Deegen, MJ Reddehase, R Holtappels
Journal of virology, 2005Am Soc Microbiol
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 …
Abstract
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 β-chain variable region (Vβ)-defined polyclonality, sorted CD8-TM cells proved to be superior by more than 2 orders of magnitude.
American Society for Microbiology