Defining the mechanism(s) of protection by cytolytic CD8 T cells against a cryptic epitope derived from a retroviral alternative reading frame

Abstract

The biological significance of protective CD8 T-cell-mediated responses against non-traditional alternative reading frame epitopes remains relatively unknown. Cytolytic CD8 T cells (CTL) specific for a non-traditional cryptic MHC class I epitope, SYNTGRFPPL, are critically involved in the protection of mice during infection with the LP-BM5 murine retrovirus. The goal of this study was to determine the functional properties of the protective SYNTGRFPPL-specific CTL during LP-BM5 infection of susceptible BALB/c CD8−/− mice. Direct infection experiments and adoptive transfer of CD8 T cells derived from perforin (pfp)−/−, IFNγ−/−, FasL−/− and, as a positive control, wild-type BALB/c mice, were utilized to assess the effector mechanisms responsible for protection. Our results indicate that SYNTGRFPPL-specific effector CTL preferentially utilize perforin-mediated cytolysis to provide protection against LP-BM5-induced pathogenesis, whereas CTL production of IFNγ is not required. Our results also suggest a minimal contribution of FasL/Fas-mediated lysis during the effector response. Collectively, these results provide insight into effector mechanisms utilized by protective CTL directed against non-traditional cryptic epitopes during disease protection.

Immunotherapy of Murine Retrovirus-Induced Acquired Immunodeficiency by CD4 T Regulatory Cell Depletion and PD-1 Blockade

“…This finding strongly suggests that the ability to develop the pathogenic CD4 T-cell response upon LP-BM5 infection, and all other cellular and molecular mechanisms for MAIDS induction and progression, are present in mice of the resistant BALB/c background, as revealed in the absence of CD8 T-cell protection (28,44,45,54,55,58). Subsequently, we demonstrated that intravenous (i.v.)…”

“…Some important features of MAIDS resemble those of human immunodeficiency virus (HIV)/AIDS in humans, including (i) early-onset hypergammaglobulinemia (hyper-Ig); (ii) splenomegaly and lymphadenopathy; (iii) dependence on CD4 T cells for initiation of disease; (iv) loss of CD4 T-cell function and subsequent severely depressed T-and Bcell responses; (v) increased susceptibility to progressive infection and mortality when exposed to normally nonpathogenic microorganisms; and (vi) the development of immunodeficiencyassociated "opportunistic" neoplasms, including end stage B-cell lymphomas (15, 35). While there are also some significant differences between AIDS and MAIDS, the LP-BM5 retroviral system has been widely used as a mouse model for human AIDS (3,32,36,42,[46][47][48].Pathogenic CD4 T effector cells are required for the initiation and progression of MAIDS, and protective CD8 T effector cells are required for MAIDS resistance (28,44,45,54,55,58). CD8 cytolytic T lymphocytes (CTLs) play a critical role in elimination of virus-infected cells and disease control in several retroviral infections, including murine AIDS (in resistant strains) and human HIV-1 infection.…”

“…Pathogenic CD4 T effector cells are required for the initiation and progression of MAIDS, and protective CD8 T effector cells are required for MAIDS resistance (28,44,45,54,55,58). CD8 cytolytic T lymphocytes (CTLs) play a critical role in elimination of virus-infected cells and disease control in several retroviral infections, including murine AIDS (in resistant strains) and human HIV-1 infection.…”

“…CD8 cytolytic T lymphocytes (CTLs) play a critical role in elimination of virus-infected cells and disease control in several retroviral infections, including murine AIDS (in resistant strains) and human HIV-1 infection. Our laboratory has defined the cellular and molecular bases of CD8 CTL-mediated protection in MAIDS-resistant mouse strains (e.g., BALB/c) (28,44,45,54,55,58), as well as insights into the requirement for CD4 T effector cell-mediated initiation/progression of viral pathogenesis in the prototypic MAIDS-susceptible strain, C57BL/6 (B6) (18-23, 39, 40). Thus, interactions between B and CD4 T cells, mediated via the ligation of CD40 and CD40L (CD154), respectively, are essential for LP-BM5-dependent pathogenesis of MAIDS, both for disease induction and for early progression (20)(21)(22).…”

Use of IRF-3 and/or IRF-7 Knockout Mice To Study Viral Pathogenesis: Lessons from a Murine Retrovirus-Induced AIDS Model

“…1). The extent of pathogenesis was calculated from established disease parameters, and a disease index was assigned, with disease severity ranging from 0 (no disease) to 5 (most-severe disease) (37)(38)(39). Infected IRF-3 Ϫ/Ϫ mice were almost as resistant as MAIDS-resistant 129 mice, whereas IRF-7 Ϫ/Ϫ mice developed disease equivalent to that seen with the susceptible B6 controls.…”