The Immune Response to Influenza Infection
Initiation of the adaptive immune response
Interferons, macrophages and NK cells slow virus replication and prevent the spread of virus during the first few days of infection. However, as is seen in individuals whose immune systems are naive to the infecting strain of virus, such as in infants or with pandemic strains of influenza, the innate immune response is not enough to stem the spread of viral infection. Thus, survival relies on the “adaptive” immune response that is initiated during this period and is essential to eliminate the virus completely. This adaptive response involves the activation of both bone marrow-derived lymphocytes (B cells) and thymus-derived lymphocytes (T cells), resulting in humoral and cell-mediated immunity, respectively. Virus-activated T cells, through a variety of cytokine mediators, stimulate B cells to differentiate and produce antibodies that are specific for the strain of virus involved.
A key feature of the adaptive immune response is the ability to store “immunological memory” for a specific pathogen. This memory provides a more rapid adaptive immune response that is specifically targeted to the antigens contained in the pathogen. Immunological memory results from differentiation of virus-specific B and T cells that are programmed to respond to specific epitopes, in this case of the viral antigens. Vaccination targets the adaptive immune response to stimulate B cells to differentiate to plasma cells that produce circulating antibodies and an army of virus-specific T cells that are activated upon re-exposure to the pathogen during a natural infection.
Structure and function of MHC
The adaptive immune response against influenza is activated when T cells recognize viral peptides presented by the major histocompatibility complex (MHC). The genetic locus that codes for MHC is a cluster of tightly linked genes, found on the short arm of chromosome 6. The MHC complex is involved in peptide binding, processing and presentation. It mediates presentation of a vast array of peptides derived from different pathogens. MHC molecules also allow the immune system to distinguish “self” from “non-self” and in this context are referred to as “transplantation antigens”. MHC genes exhibit a high degree of polymorphism and, within the individual genotype, have the capacity to produce MHC molecules that bind to a specific subset of pathogen-derived peptides determined by the MHC molecules of the individual. Thus, each individual exhibits a unique set of MHC molecules and the diversity of the MHC increases the likelihood that a protective adaptive immune response can be mounted by most people.
Class I and class II MHC molecules are glycoproteins expressed on the cell surface, and consist of cytoplasmic, transmembrane and extracellular portions. The overall structure of individual MHC molecules enables the immune system to distinguish self from non-self. Indeed, on this basis T cells are able to recognize non-self MHC molecules – for example, in the case of rejection after organ transplantation. The pathogen specificity of MHC is largely concentrated in the peptide-binding cleft of the molecules, where peptides from the pathogen are presented to T cells. These T cells are only able to recognize these peptide antigens when they are presented by self-MHC molecules (self-MHC restriction). CD8-positive T cells recognize antigen only in association with class I MHC molecules (class I MHC-restricted), while CD4-positive T cells recognize antigen only in association with class II MHC molecules (class II MHC-restricted).
Antigen processing and presentation
MHC molecules present peptide fragments derived from viral proteins either degraded or synthesized inside the cell, and the MHC–peptide complex is transported to the cell surface, where the complex can be recognized by the T cell receptor. 12 x TJ Braciale, LA Morrison, MT Sweetser, et al.. Antigen presentation pathways to class I and class II MHC-restricted T lymphocytes. Immunol Rev 98 (1987) (95 - 114) Crossref. Antigen-presenting cells (APCs) have different pathways of antigen processing for class I and class II MHC, and different requirements for loading peptides from live or killed virus onto the MHC class I molecules (see Figure 17 ). In contrast to other APCs, dendritic cells (DCs) are able to present peptides derived from any form of virus, including killed viruses, through what have been defined as “non-classical” pathways of antigen processing and presentation. The ability of DCs to deliver viral protein antigens from the endosomal compartment to the cell cytosol for processing in the MHC class I pathway is important in the context of the development of new inactivated influenza vaccines that will induce not only an adequate antibody response but also CTL activity, as discussed further in
Figure 17 source: Adapted from Abbas AK, Lichtman AH. Basic Immunology, 2nd edn. WB Saunders, 2004 with permission from Elsevier.
References in context
MHC molecules present peptide fragments derived from viral proteins either degraded or synthesized inside the cell, and the MHC–peptide complex is transported to the cell surface, where the complex can be recognized by the T cell receptor.12 Antigen-presenting cells (APCs) have different pathways of antigen processing for class I and class II MHC, and different requirements for loading peptides from live or killed virus onto the MHC class I molecules (see Figure 17).
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Professional APCs process and present antigen to CD4-positive T cells (T helper cells) in association with MHC II, and to CD8-positive T cells (CTLs) in association with MHC I. APCs express high levels of MHC II (expressed almost exclusively on APCs, such as DCs and macrophages, and on B cells) and variable amounts of MHC I depending on the degree of upregulation of MHC I by interferon-gamma (IFN-γ). DCs represent the key professional APCs due to their exquisite ability to activate T cells through presentation of antigen on MHC molecules (involving both classical and non-classical pathways) and to further activate T cells by a variety of costimulatory molecules. Helper T cells recognize peptides presented by MHC II on the APC. This interaction is critical for the influenza-specific T helper cell responses necessary for the development of both B cell and CTL memory. CTLs recognize viral peptides in conjunction with MHC I; MHC I is expressed not only on APC but also on most other cells in the body and thus when combined with viral peptides provide the stimulus for CTL-mediated killing of virus-infected cells in the effector phase of the cell-mediated immune response, as discussed below.
References in context
|TJ Braciale, LA Morrison, MT Sweetser, et al..||Antigen presentation pathways to class I and class II MHC-restricted T lymphocytes. Crossref.||Immunol Rev 98 (1987) (95 - 114)||1987|