Subdominant CD8 T-Cell Epitopes Account for Protection against Cytomegalovirus Independent of Immunodomination

Abstract

Cytomegalovirus (CMV) infection continues to be a complication in recipients of hematopoietic stem cell transplantation (HSCT). Preexisting donor immunity is recognized as a favorable prognostic factor for the reconstitution of protective antiviral immunity mediated primarily by CD8 T cells. Furthermore, adoptive transfer of CMV-specific memory CD8 T (CD8-T M ) cells is a therapeuticAllogeneic hematopoietic stem cell transplantation (HSCT) combined with donor lymphocyte infusion is a promising therapeutic option against hematologic malignancies (2, 29). Reactivated cytomegalovirus (CMV) infection resulting in CMV disease, in particular, interstitial pneumonia, is a frequent and severe complication (6,18,56). As shown by Emery (13) and reviewed recently by Wills et al. (65), the risk of HSCT-associated CMV disease is basically defined by the CMV status of transplantation donor (D) and recipient (R). The combination D Ϫ R Ϫ bears no intrinsic CMV risk, while the combinations D ϩ R Ϫ and D Ϫ R ϩ are at risk of reactivating latent CMV from the donor transplant and from recipient tissues, respectively. Although a combination D ϩ R ϩ is prone to an additive risk of reactivation, CMV disease nevertheless occurs less frequently in D ϩ R ϩ than in D Ϫ R ϩ , indicating a protective effect of preexisting donor immunity (13). That adoptive transfer of CMVspecific CD8 memory T (CD8-T M ) cells is a promising approach for preventing CMV reactivation and disease has been established in the murine CMV (mCMV) model (50,53,55,60; reviewed in references 20 and 22) and was confirmed for human CMV (hCMV) in clinical trials (8,10,45,57,64).A potential problem so far never investigated systematically is the impact of an antigenic mismatch between the donorderived and the recipient-derived CMV variant in a D ϩ R ϩ combination. Obviously, antigenic mismatch is not an issue in a D ϩ R Ϫ combination of HSCT, since here priming of the donor and infection of the recipient are by the same virus. In a D ϩ R ϩ combination, however, donor-CMV and recipient-CMV are likely to differ due to the individuality of the infection history. CMV is often acquired perinatally or in early childhood. So, donor and recipient have usually harbored their respective CMV variants for many years or even decades. They were most likely infected by different variants ab initio, and further divergence may have resulted from the accumulation of mutations during productive primary infection and during multiple intermittent recurrences later on. Thus, a D ϩ R ϩ combination may more precisely be written as D Var1 R Var2 . Although, of course, not all differences in the proteomes of CMV variants concern CD8 T-cell epitopes, antigenic mismatch is a realistic scenario as indicated by antigenic variance of hCMV clinical isolates (11,32) as well as by CD8 T-cell epitope mutations detected in mCMV isolates from outbred mice (34). Clearly,

Epitope-specific in vivo protection against cytomegalovirus disease by CD8 T cells in the murine model of preemptive immunotherapy

“…Absence of sensitization by MEF exposed to UV light-inactivated virus showed that viral gene expression is required, thus excluding a possible recognition of virion protein-derived peptides [12,13] as well as of cellular peptides induced by the signaling and the resulting global change of the cellular transcriptome that is associated with the viral entry process (for reviews see [14,15]). In accordance with all what we have learnt about immunoevasins encoded by mCMV (for reviews see [5,10,16,17], as well as the article by Doom and Hill in this issue of MMI), MEF infected with mCMV-WT.BAC stimulated only a minor fraction of the IE1-specific CTL in this T cell line, most likely those with the highest avidity. Absence of viral immunoevasins m04/gp34 and m06/gp48 in MEF infected with the respective deletion mutant mCMVDm04 + 06 improved peptide presentation and thus recruited also CTL with somewhat lower avidity.…”

“…Another striking finding revealed by the immunotherapy studies was the apparent irrelevance of the type of epitope; essentially all CTL lines (CTLL) protected in adoptive transfer assays regardless of the immunodominance status IgG1-iso of the respective antigenic peptide (for reviews, see [10] and the accompanying article by Holtappels et al in this issue of MMI). We therefore began to wonder if the observed protection was based on TCR-mediated recognition of MHC class-I presented antigenic peptide at all.…”

Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model

“…74,82 CMV infection elicits a broad CD8 1 T-cell response that is specific for an array of viral antigens. [90][91][92] However, in the brain, the MCMV-directed immune response seems to be quite focused. In newborn BALB/c mice, approximately 10% of brain-infiltrating CD8 1 T cells are directed to a single, immunodominant IE1 epitope at the peak of the response.…”

Analysis of the Conservation of T Cell Receptor Alpha and Beta Chain Variable Regions Gene in pp65 Peptide-Specific HLA-A*0201-Restricted CD8+ T Cells

“…It has been reported that there are clonal expansions of certain T cell subgroups in the peripheral blood of CMV infectors in the acute phase (2). These T cells are considered as CMV-specific cytotoxic T lymphocytes (CTL), which play an important role in inhibiting CMV infection and reactivation (3).…”