Under normal healthy conditions, there are relatively few lymphocytes in the lungs. However, upon infection, lymphocytes are recruited in large numbers. Natural killer (NK) cells constitute one of the body's first cells recruited into any tissue as a defense against viral infection. They play a key role in killing virus-infected cells that lack or have altered expression of cell surface MHC-I ligands, which is typical during the early phase of a viral infection (Chambers et al., 1998; Lanier, 1998). The number and cytolytic activity of NK cells is highly correlated with natural resistance to viral challenge. Chronically low NK activity in humans is associated with increased incidence and duration of infection and decreased survival during influenza viral infections (Stein-Streilein et al., 1989).
In addition to the NK cell, both T and B lymphocytes are involved in recovery from influenza infection and with protection against reinfection with the same strain of virus. However, in contrast with the NK cell, which does not recognize influenza viral antigens in an antigen-specific manner, the T- and B-cell responses are restricted to virus-specific subclones. Whereas the NK cell traffics to the lung by the initial alarm signal sounded by Toll-like receptor activation, the T and B cells have to be selected for activation based on their antigen specificity. This occurs in secondary lymph nodes that drain the site of infection. With regard to influenza infection of the lung, this is the mediastinal, the superficial cervical, and the deep cervical lymph nodes. These lymph nodes serve as the site where the antigen-specific lymphocytes are driven to proliferate (e.g., clonal expansion); it is also the site where they mature so that once antigen is encountered, they are competent to mediate their respective effector functions. Because of their killing power and potential ability to cause immunopathology if not adequately controlled, antigen-specific responses are tightly coordinated. It is generally acknowledged that the conductor of the adaptive immune response is the CD4+ helper T cell which is the first antigen-specific cell activated in response to influenza virus.
In turn, it drives expansion and activation of the influenza-specific CD8+ T cells and the antibody-producing B cells.
Clonal activation of naïve CD4+ cells requires antigen-specific signaling through the T-cell receptor (TCR) as well as signaling through multiple costimulatory molecules (Chambers and Allison, 1997; Lanzavecchia et al., 1999). This is provided by cells whose job is to acquire and process viral antigen. More specifically, dendritic cells at the site of infection in the lung engulf viral particles, mature in response to inflammatory signals, migrate to draining lymph nodes, and present antigen in the context of MHC class II molecules to activate naïve virus-specific CD4+ cells (Fonteneau et al., 2003; Lund et ai, 2004).
Depending on the type of antigen encountered and the microenvironment where the antigen is presented to the antigen-specific CD4+ T cell, the immune response may differ dramatically. If antigen is encountered by the CD4+ cell in the presence of IL-12, and IFN-y, naïve CD4+ cells differentiate into T helper 1 (Th1) cells that produce quantities of IFN-y, IL-2, and TNF-a (Deng et al., 2004).Alternatively, activation of the naïve CD4+ T cell in the presence of IL-4 induces the development of Th2 effectors that secrete IL-4, IL-5, and IL-13 (Oran and Robinson, 2004). Although most infections will drive the development of both types of T cells, viral infections such as that with influenza A virus are known to predominantly induce Th1 or type 1 immunity (Cella et al., 2000; Lopez et al., 2002).
In turn, clonal expansion of influenza virus-specific CD4+ T cells of the Th1 subtype promotes the activation of cytotoxic CD8+ T cells (Maillard et al., 2002; Fonteneau et al., 2003). Such T cells play a major role in the clearance of influenza virus from the lungs via an MHC class I-dependent cytotoxic mechanism involving perforin and Fas (Topham et al., 1997). These molecules serve simply to kill the virus infected cell. The CD8+ T cell is important for recovery from infection, as there is elevated viral replication, morbidity, and mortality in mice that lack CD8+ T cells (Liu et al., 2003).
The Th1 CD4+ T cell also drives B-cell differentiation and expansion into plasma cells that produce subclasses of antibody (i.e., IgA and IgG2a) for antibody-dependent cellular cytotoxicity mediated by NK cells (Hashimoto et al., 1983; Jegerlehner et al., 2004). Impairment of B-cell development slows clearance of influenza viral antigen but has no substantial influence on survival or recovery from infection (Gerhard et al., 1997). Although not necessary for recovery from infection, the strength of antigen-specific B-cell expansion is revealed upon reinfection with antigenically similar strains of influenza infection. It showcases the power of immunological memory.
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