Biology subjects

Reddehase, M. J.

Publications and source records attributed to Reddehase, M. J..

3 recordsLinked to original sources

bioRxiv2024

Cytomegalovirus inhibitors of programmed cell death prevent a contribution of antigen cross-presentation to the priming of antiviral CD8 T cells

CD8 T cells are the predominant effector cells of adaptive immunity in preventing cytomegalovirus (CMV) multiple-organ disease caused by cytopathogenic tissue infection. The mechanism by which CMV-specific, naive CD8 T cells become primed and clonally expand is of fundamental importance for our understanding of CMV immune control. For CD8 T-cell priming, two pathways have been identified: direct antigen presentation by infected professional antigen-presenting cells (pAPCs) and antigen cross-presentation by uninfected pAPCs that take up antigenic material derived from infected tissue cells. Studies in mouse models using murine CMV (mCMV) and precluding either pathway genetically or experimentally have shown that, in principle, both pathways can congruently generate the mouse MHC/H-2 class-I-determined epitope-specificity spectrum of the CD8 T-cell response. Own recent studies, however, have shown that direct antigen presentation is the canonical pathway when both are accessible. This raised the question of why antigen cross-presentation is ineffective even under conditions of high virus replication thought to provide high amounts of antigenic material for feeding cross-presenting pAPCs. As delivery of antigenic material for cross-presentation is associated with programmed cell death, and as CMVs encode inhibitors of different cell death pathways, we pursued the idea that these inhibitors restrict antigen delivery and thus CD8 T-cell priming by cross-presentation. To test this hypothesis, we compared the CD8 T-cell responses to recombinant mCMVs lacking expression of the apoptosis-inhibiting protein M36 or the necroptosis-inhibiting protein M45 with responses to wild-type mCMV and revertant viruses expressing the respective cell death inhibitors. The data reveal that increased programmed cell death caused by deletion of either M36 or M45 improves CD8 T-cell priming in mice capable of antigen cross-presentation but not in a mutant mouse strain unable to cross-present. These findings strongly support the conclusion that CMV cell death inhibitors restrict the priming of CD8 T cells by antigen cross-presentation. Author SummaryIn patients as well as in experimental mouse models, CD8 T cells represent the most potent antiviral effector cells in preventing CMV disease in immunocompromised recipients of hematopoietic cell transplantation. Despite the clinical relevance of mounting a protective response, the mode of CMV antigen presentation to naive CD8 T cells remained unclear. In principle, naive CD8 T cells can be sensitized through "direct antigen presentation" on the surface of infected professional antigen-presenting cells (pAPCs) or through "antigen cross-presentation" by uninfected pAPCs that take up antigenic material derived from infected cells following cell death. As CMVs are cytopathogenic, eventually killing their host cells, and as they encode immune evasion proteins interfering with the MHC/HLA class-I pathway of direct antigen presentation in infected cells, it was reasonable to propose a dominant role for antigen cross-presentation. Mouse models precluding either pathway, however, revealed that both can raise an equivalent CD8 T-cell response, and recent work has identified direct antigen presentation as the canonical pathway taken when both are accessible. Here we show that virus-encoded inhibitors of two programmed cell death modalities, apoptosis and necroptosis, prevent an antigen release sufficient for a notable cross-presentation. This answers a long-debated open question in CMV immunology.

immunology↗

bioRxiv2023

Direct Antigen Presentation is the Canonical Pathway of Cytomegalovirus CD8 T-cell Priming Regulated by Balanced Immune Evasion Mounting a Strong Antiviral Response

CD8 T cells are the main antiviral effectors of the adaptive immune response to cytomegaloviruses (CMVs) in confining acute infection and in long-term surveillance of latent infection. An unresolved issue of debate, with diametrically opposite conclusions, is the mechanism by which CMV-specific naive CD8 T cells are primed. The idea of priming by antigen cross-presentation through uninfected professional antigen presenting cells taking up viral proteins derived from infected cells was based on the observation that the net response is not improved when direct presentation is enhanced by deletion of viral immune evasion genes affecting the classical MHC class-I pathway of antigen presentation. Redundance of priming mechanisms has been demonstrated by experimental models in which either pathway has been rendered inaccessible, so that both pathways are, in principle, capable of priming CD8 T cells. For studying CMV-specific priming in the normal host competent in both antigen presentation pathways, we took the novel approach to enhance instead of delete immune evasion protein expression. Surprisingly, the net magnitude of the CD8 T-cell response in the regional lymph node draining a local site of infection was identical for the contrasts of reduced or enhanced direct antigen presentation. At first glance, this may lead one to conclude that direct presentation plays no role in priming. This interpretation, however, is incompatible with the finding that an intermediate extent of direct antigen presentation, as it exists for wild-type virus, resulted in the best CD8 T-cell response. Our findings thus revealed an essential positive role of a balanced viral immune evasion in mounting a strong antiviral immune response. This novel insight sheds a completely new light on the acquisition of viral immune evasion genes during virus-host co-evolution.

immunology↗

bioRxiv2023

Immunotherapy of cytomegalovirus infection by low-dose adoptive transfer of antiviral CD8 T cells relies on substantial post-transfer expansion of central memory cells but not effector-memory cells

Cytomegaloviruses (CMVs) are host species-specific in their replication. It is a hallmark of all CMVs that productive primary infection is controlled by concerted innate and adaptive immune responses in the immunocompetent host. As a result, the infection usually passes without overt clinical symptoms and develops into latent infection, referred to as latency. During latency, the virus is maintained in a non-replicative state from which it can reactivate to productive infection under conditions of waning immune surveillance. In contrast, infection of an immunocompromised host causes CMV disease with viral multiple-organ histopathology resulting in organ failure. Primary or reactivated CMV infection of hematopoietic cell transplantation (HCT) recipients in a "window of risk" between therapeutic hematoablative leukemia therapy and immune system reconstitution remains a clinical challenge. Studies in the mouse model of experimental HCT and infection with murine CMV (mCMV), followed by clinical trials in HCT patients with human CMV (hCMV) reactivation, have revealed a protective function of virus-specific CD8 T cells upon adoptive cell transfer (AT). Memory CD8 T cells derived from latently infected hosts are a favored source for immunotherapy by AT. Strikingly low numbers of these cells were found to prevent CMV disease, suggesting either an immediate effector function of few transferred cells or a clonal expansion generating high numbers of effector cells. In the murine model, the memory population consists of resting central memory T cells (TCM), as well as of conventional effector-memory T cells (cTEM) and inflationary effector-memory T cells (iTEM). iTEM, increase in numbers over time in the latently infected host, a phenomenon known as memory inflation (MI). They thus appeared to be a promising source for use in immunotherapy. However, we show here that iTEM contribute little to the control of infection after AT, which rests almost exclusively on a superior proliferation potential of TCM. Author SummaryImmunotherapy of reactivated cytomegalovirus infection in immunocompromised HCT recipients by adoptive transfer (AT) of antiviral CD8 T cells is the last resort to fight virus variants that have acquired resistance to standard antiviral drugs. Provision of cell numbers high enough for clearance of productive infection remains a logistical limitation for AT to become clinical routine. Although use of donor memory CD8 T cells has become the standard in clinical AT, little is known about the relative antiviral efficacies of memory CD8 T-cell activation subsets, such as central memory cells (TCM) and different populations of effector-memory cells (TEM). A reliable quantitative comparison of the antiviral efficacies of memory CD8 T-cell subsets is precluded in clinical investigation, because independent cohorts of AT donors and AT recipients unavoidably differ in many genetical, immunological, and virological variables. Therefore, this is a question for which a preclinical animal model is predestined. We show here in the well-established mouse model of low-dose AT that CMV infection is by far most efficiently controlled by virus-specific TCM, based on a superior potential to proliferate even in extra-lymphoid tissue to prevent virus spread. For clinical AT, our data provide an argument to favor transfer of sorted TCM rather than TEM.

immunology↗