Reconstitution of CD8 T Cells Protective against Cytomegalovirus in a Mouse Model of Hematopoietic Cell Transplantation: Dynamics and Inessentiality of Epitope Immunodominance

Abstract

Successful reconstitution of cytomegalovirus (CMV)-specific CD8+ T cells by hematopoietic cell transplantation (HCT) gives a favorable prognosis for the control of CMV reactivation and prevention of CMV disease after hematoablative therapy of hematopoietic malignancies. In the transient immunocompromised state after HCT, pre-emptive cytoimmunotherapy with viral epitope-specific effector or memory CD8+ T cells is a promising option to speed up antiviral control. Despite high-coding capacity of CMVs and a broad CD8+ T-cell response on the population level, which reflects polymorphism in major histocompatibility complex class-I (MHC-I) glycoproteins, the response in terms of quantity of CD8+ T cells in any individual is directed against a limited set of CMV-encoded epitopes selected for presentation by the private repertoire of MHC-I molecules. Such epitopes are known as “immunodominant” epitopes (IDEs). Besides host immunogenetics, genetic variance in CMV strains harbored as latent viruses by an individual HCT recipient can also determine the set of IDEs, which complicates a “personalized immunotherapy.” It is, therefore, an important question if IDE-specific CD8+ T-cell reconstitution after HCT is critical or dispensable for antiviral control. As viruses with targeted mutations of IDEs cannot be experimentally tested in HCT patients, we employed the well-established mouse model of HCT. Notably, control of murine CMV (mCMV) after HCT was comparably efficient for IDE-deletion mutant mCMV-Δ4IDE and the corresponding IDE-expressing revertant virus mCMV-Δ4IDE-rev. Thus, antigenicity-loss mutations in IDEs do not result in loss-of-function of a polyclonal CD8+ T-cell population. Although IDE deletion was not associated with global changes in the response to non-IDE epitopes, the collective of non-IDE-specific CD8+ T-cells infiltrates infected tissue and confines infection within nodular inflammatory foci. We conclude from the model, and predict also for human CMV, that there is no need to exclusively aim for IDE-specific immunoreconstitution.

Insufficient Antigen Presentation Due to Viral Immune Evasion Explains Lethal Cytomegalovirus Organ Disease After Allogeneic Hematopoietic Cell Transplantation

“…The idea that a contribution by L d -restricted CD8 + T cells is quantitatively or qualitatively critical for antiviral protection is also untenable in face of the finding that the infection is controlled in HvG-HCT in which the recipients cannot present L d -restricted antigenic peptides (Alterio de Goss et al, 1998;this report). Finally, protective activity of polyclonal mCMV-specific CD8 + T cells is so redundant that even deletion of immunodominant antigenic peptides presented by K d , D d , and L d is tolerated (Holtappels et al, 2008(Holtappels et al, , 2016Ebert et al, 2012a).…”

Peptide Processing Is Critical for T-Cell Memory Inflation and May Be Optimized to Improve Immune Protection by CMV-Based Vaccine Vectors

“…Predictive algorithms to identify epitope insertion sites with optimized antigenic processing [42], have been recently applied to score peptide processing of natural and modified epitopes expressed by MCMV [43]. However, published data argue that the proteasome needs to cleave peptides very precisely behind the anchoring amino acid at the C-terminus of an epitope (reviewed in [44]), whereas additional amino acids present on the N-terminal end of the epitope precursor peptide may be trimmed by aminopeptidases upon TAP-mediated transport into the ER [45].…”

γδ T Cell-Mediated Immunity to Cytomegalovirus Infection

“…In the absence of adoptive T cells therapy, mortality can be prevented by transferring high doses of HSC into the host. By means of a recombinant virus in which four (BALB/c) immunodominant epitopes (IDEs) were functionally deleted, the Reddehase group elegantly showed that reconstitution of IDE-specific CD8 + T cells is not essential for antiviral control in infected HSCT hosts ( 80 ). Efficient protection in the absence of IDE was also evidenced in the CD8 + T cells adoptive transfer scenario ( 81 ).…”