Immunologic recognition of influenza virus-infected cells. II. Expression of influenza A matrix protein on the infected cell surface and its role in recognition by cross-reactive cytotoxic T cells

Two distinct subpopulations of cytotoxic T cells are generated in the primary or secondary response of mice to type A influenza viruses. One subpopulation is specific for the immunizing virus strain. The other subpopulation shows a high degree of cross-reactivity for heterologous type A virus of a different subtype. This report examines the possibility that distinct influenza virus antigens, expressed on the surface of the infected cell, are recognized by the different subpopulations of influenza-specific cytotoxic T cells. Data are presented which demonstrate that influenza A matrix protein, an internal virion antigen, is detectable on the surface of target cells infected with influenza A viruses of different subtypes. Since this viral antigen is type specific, i.e., serologically cross-reactive among all type A influenza viruses, it could serve as the target for cross-reactive cytotoxic T cells. To further examine the specificity of the two cytotoxic T-cell subpopulations, experiments were carried out by using the inhibitor of glycoprotein synthesis - 2-Deoxy-D-Glucose 2-DG. These experiments examine first the effect of 2-DG on the expression of influenza matrix protein and viral glycoprotein on the infected cell surface and second, the susceptibility of 2-DG-treated target cells to lysis by cytotoxic T cells. 2-DG inhibits the expression of the viral hemagglutinin glycoprotein on the cell surface but does not inhibit the expression of the nonglycosylated matrix protein. Furthermore, inhibition of glycoprotein synthesis in infected target cells abrogates the reactivity of infected target cells to lysis by virus strain-specific but not cross- reactive cytotoxic T cells. These findings suggest that the influenza glycoproteins (hemagglutinin and/or neuraminidase) and the nonglycosylated matrix protein are the targets for the virus strain- specific and cross-reactive cytotoxic T cells, respectively. These results are discussed in the light of available information on influenza virus structure and the biology of influenza infection and in terms of current models for cytotoxic T-cell recognition of virus-infected cells

Regulating the adaptive immune response to respiratory virus infection

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.Recent years have seen several advances in our understanding of immunity to virus infection of the lower respiratory tract, including to influenza virus infection. Here, we review the cellular targets of viruses and the features of the host immune response that are unique to the lungs. We describe the interplay between innate and adaptive immune cells in the induction, expression and control of antiviral immunity, and discuss the impact of the infected lung milieu on moulding the response of antiviral effector T cells. Recent findings on the mechanisms that underlie the increased frequency of severe pulmonary bacterial infections following respiratory virus infection are also discussed

T Cell Responses during Acute Respiratory Virus Infection

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.The T cell response is an integral and essential part of the host immune response to acute virus infection. Each viral pathogen has unique, frequently nuanced, aspects to its replication, which affects the host response and as a consequence the capacity of the virus to produce disease. There are, however, common features to the T cell response to viruses, which produce acute limited infection. This is true whether virus replication is restricted to a single site, for example, the respiratory tract (RT), CNS etc., or replication is in multiple sites throughout the body. In describing below the acute T cell response to virus infection, we employ acute virus infection of the RT as a convenient model to explore this process of virus infection and the host response. We divide the process into three phases: the induction (initiation) of the response, the expression of antiviral effector activity resulting in virus elimination, and the resolution of inflammation with restoration of tissue homeostasis

Incomplete Cd8+ T Lymphocyte Differentiation as a Mechanism for Subdominant Cytotoxic T Lymphocyte Responses to a Viral Antigen

CD8+ cytotoxic T lymphocytes (CTLs) recognize antigen in the context of major histocompatibility complex (MHC) class I molecules. Class I epitopes have been classified as dominant or subdominant depending on the magnitude of the CTL response to the epitope. In this report, we have examined the in vitro memory CTL response of H-2d haplotype murine CD8+ T lymphocytes specific for a dominant and subdominant epitope of influenza hemagglutinin using activation marker expression and staining with soluble tetrameric MHC–peptide complexes. Immune CD8+ T lymphocytes specific for the dominant HA204-210 epitope give rise to CTL effectors that display activation markers, stain with the HA204 tetramer, and exhibit effector functions (i.e., cytolytic activity and cytokine synthesis). In contrast, stimulation of memory CD8+ T lymphocytes directed to the subdominant HA210-219 epitope results in the generation of a large population of activated CD8+ T cells that exhibit weak cytolytic activity and fail to stain with the HA210 tetramer. After additional rounds of restimulation with antigen, the HA210-219–specific subdominant CD8+ T lymphocytes give rise to daughter cells that acquire antigen-specific CTL effector activity and transition from a HA210 tetramer–negative to a tetramer-positive phenotype. These results suggest a novel mechanism to account for weak CD8+ CTL responses to subdominant epitopes at the level of CD8+ T lymphocyte differentiation into effector CTL. The implications of these findings for CD8+ T lymphocyte activation are discussed

Generation of virus-specific cytotoxic T cells in vitro II. Induction requirements with functionally inactivated virus preparations

Using noninfectious Sendai virus preparations after selective enzymatic digestion of either of the two viral envelope glycoproteins, it was possible to study the effect of different virion-cell membrane interactions on virus-specific cytotoxic T lymphocyte (CTL) induction in vitro. Three different virus preparations having capacity for virus- cell fusion, for virus-cell adsorption or lacking the ability to bind to cell membranes, were all active in the generation of virus-specific primary and secondary cytotoxic T cells, when added to the culture. Investigations on the responder cell requirements during CTL induction revealed that activation by addition of virions lacking the capacity to bind to cells was sensitive to the depletion of adherent cells. When virions with fusion and binding capacity were presented on tumor stimulator cells, different requirements with respect to adherent cells were obtained in the primary and secondary CTL response to Sendai virus. The data indicate that different viral antigen-cell membrane interactions govern the activation phase and effector phase of antigen- primed T cell populations, while sensitization of unprimed cells is dependent on the presence of adherent, perhaps antigen-presenting cells

Type I interferon signaling facilitates the development of IL-10-producing effector CD8+ T cells during influenza virus infection

Recent evidence has suggested that IL-10-producing effector CD8+ T cells play an important role in regulating excessive inflammation during acute viral infections. However, the cellular and molecular cues regulating the development of IL-10-producing effector CD8+ T cells are not completely defined. Here, we show that type I interferons (IFNs) are required for the development of IL-10-producing effector CD8+ T cells during influenza virus infection in mice. We find that type I IFNs can enhance IL-27 production by lung APCs, thereby facilitating IL-10-producing CD8+ T-cell development through a CD8+ T-cell-nonautonomous way. Surprisingly, we also demonstrate that direct type I IFN signaling in CD8+ T cells is required for the maximal generation of IL-10-producing CD8+ T cells. Type I IFN signaling in CD8+ T cells, in cooperation with IL-27 and IL-2 signaling, promotes and sustains the expression of IFN regulatory factor 4 (IRF4) and B-lymphocyte-induced maturation protein-1 (Blimp-1), two transcription factors required for the production of IL-10 by effector CD8+ T cells. Our data reveal a critical role of the innate antiviral effector cytokines in regulating the production of a regulatory cytokine by effector CD8+ T cells during respiratory virus infection