Parameters determining the efficacy of adoptive CD8 T-cell therapy of cytomegalovirus infection

Abstract

Reactivation of latent cytomegalovirus (CMV) in the transient state of immunodeficiency after hematopoietic cell transplantation (HCT) is the most frequent and severe viral complication endangering leukemia therapy success. By infecting the bone marrow (BM) stroma of the transplantation recipient, CMV can directly interfere with BM repopulation by the transplanted donor-derived hematopoietic cells and thus delay immune reconstitution of the recipient. Cytopathogenic virus spread in tissues can result in CMV disease with multiple organ manifestations of which interstitial pneumonia is the most feared. There exists a 'window of risk' between hematoablative treatment and reconstitution of antiviral immunity after HCT, whereby timely reconstitution of antiviral CD8 T cells is a recognized positive prognostic parameter for the control of reactivated CMV infection and prevention of CMV disease. Supplementation of endogenous reconstitution by adoptive cell transfer of 'ready-to-go' effector and/or memory virus epitope-specific CD8 T cells is a therapeutic option to bridge the 'window of risk.' Preclinical research in murine models of CMV disease has been pivotal by providing 'proof of concept' for a benefit from CD8 T-cell therapy of HCT-associated CMV disease (reviewed in Holtappels et al. Med Microbiol Immunol 197:125-134, 2008). Here, we give an update of our previous review with focus on parameters that determine the efficacy of adoptive immunotherapy of CMV infection by antiviral CD8 T cells in the murine model.

Noncanonical Expression of a Murine Cytomegalovirus Early Protein CD8 T-Cell Epitope as an Immediate Early Epitope Based on Transcription from an Upstream Gene

“…Surprisingly, however, a significant proportion of the m164-CTL, supposedly those with the highest functional avidity [25,31], also recognized target cells arrested in the IE phase. Recognition in both the IE and the E phase was abolished after infection with the epitope deletion virus mCMV-m164Ala, thereby excluding the theoretical possibility that inhibitor treatment of infected target cells might have induced T cell receptor (TCR)-independent, non-epitope specific signaling that activates CTLL.…”

“…Interestingly, cytolytic T lymphocytes (CD8 + CTL) of an m164-specific CTL line (m164-CTLL) recognized infected fibroblasts in the E phase despite all immune evasion molecules being expressed, a finding that was explained by high numbers of pMHC-I (m164 peptide-D d ) complexes exhausting the inhibitory capacity of the immune evasion proteins, thus allowing the escape of some of the pMHC-I complexes to the cell surface sufficient for recognition [23]. Importantly, in an experimental approach of CMV immunotherapy (for reviews, see [24,25]), m164-CTLL proved to protect against multiple organ CMV disease upon adoptive cell transfer into infected, immunocompromised recipient mice [11]. …”

TCR-Ligand k off Rate Correlates with the Protective Capacity of Antigen-Specific CD8 + T Cells for Adoptive Transfer

“…MCMV-specific T-cell lines were generated and restimulated similarly with 10 −8 or 10 −10 M of the m164 257-265 peptide (27). …”

“…For the MCMV protection assay (26, 27, 30), 10 6 cells from the indicated cell line were transferred i.v. into 8- to 10-week-old female BALB/c recipients which were immunocompromised by total-body γ-irradiation with a single dose of 6.5 Gy before transfer.…”

Encapsulation of an EP67-Conjugated CTL Peptide Vaccine in Nanoscale Biodegradable Particles Increases the Efficacy of Respiratory Immunization and Affects the Magnitude and Memory Subsets of Vaccine-Generated Mucosal and Systemic CD8+ T Cells in a Diameter-Dependent Manner

“…The second possibility is that the same number of the most protective memory subsets of CD8 + T cells against MCMV infection were generated to similar levels by MP and NP despite differences in total magnitude. This is supported by evidence that adoptive transfer of epitope-specific TCM including pp89 are the most effective against primary infection with MCMV 64 and our observation that NP increased the magnitude of pp89-specific CD8 + T cells above MP in the spleen (0.81% vs. 0.61%) (Fig.1B) but had the same levels of total TCM (CD127 + KLRG1 − CD62L + ) (~0.38% of total CD8a + CD44 HI Tet-pp89 + cells; NP: ~45.9% of 0.81% and MP: ~62% of 0.61%) (Fig.3C). The third possibility is that differences in protection by CD127/KLRG1/CD62L memory subsets becomes more apparent at later time points when potentially short-lived memory subsets are no longer around to provide protection.…”