Cellular Involvement In Immune Responses Biology Essay

Published:

This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.

The cytokines and chemokines produced during an immune response to viral infections are capable of recruiting a wide range of innate and adaptive cell types. These cells can be broadly divided into three groups, cells of the innate response, cells that bridge the innate and adaptive response and cells of the adaptive response.

Cells of the innate immune response

During a primary respiratory virus infection, the immune cells recruited to the lung are predominantly neutrophils, NK cells, alveolar macrophages (AMs) and dendritic cell (DCs). AMs and DCs act as antigen presenting cells and will be further discussed in Chapter 1.5.

Neutrophils

Neutrophils are produced in the bone marrow and are the predominant granulocyte in the circulation {Bainton, 1971 #116}. The primary function of neutrophils in the innate immune response is to contain and kill invading microbial pathogens {Suzuki, 2008 #120}(Nathan 2006). Neutrophils are important in pulmonary host defence as they respond to chemotactic stimuli following infection and traffic in large numbers to the lung where they function as phagocytes. They migrate to the lung parenchyma via the vascular endothelium and basement membrane in a multistep process involving the endothelial expression of adhesion molecules, which include selectins, integrins, and Ig superfamily members. The initial adhesion of neutrophils to the inflamed vascular endothelium is mediated by P- and E- selectins, which tether the neutrophils, thus increasing their exposure to chemotactic and pro-inflammatory agents. This leads to an enhancement in integrin avidity and affinity. The integrin receptors (principally β2 and β3), have been shown to be the major adhesive molecules that mediate neutrophil activation and firm integrin adhesion leads to the arrest of neutrophils on the endothelial surface. This is followed by migration into the sub-endothelial space, where they release reactive oxygen and nitrogen intermediates and granule constituents into the lung tissue, leading to the elimination of pathogens. Neutrophil chemotaxis is in turn dependant on the production of chemokines. Although neutrophils have long been considered primary effector cells against microbial infections, they also make up the predominant cell type in the early innate inflammatory response to influenza virus infection of humans, ferrets and mice {Sweet, 1980 #117}. However, the role that neutrophils play in innate host defence and respiratory virus clearance has not been well defined as few reports have analysed its role against generalized virus infections. Recently, studies by Tate et al and Fujisawa et al have established an essential role for neutrophils in viral clearance using mice depleted of neutrophils {Fujisawa, 2001 #7}{Tate, 2008 #12}. They have shown that neutrophil-depleted mice suffered from rapid weight loss, pulmonary inflammation, pneumonia, and death. Taken together their data suggest that neutrophils play a critical role in limiting influenza virus replication during the early and late phase of infection, providing a protective role against influenza virus.

Natural killer cells

Natural killer (NK) cells represent a distinct subset of lymphoid cells that have innate immune functions (Cerwenka 2001). They are derived from the bone marrow and circulate in the blood. NK cells can respond to infection either directly or indirectly. They respond directly by recognizing influenza virus- and parainfluenza virus-infected cells that express ligands for NK cell receptors {Lanier, 2003 #121}, and indirectly by interacting with dendritic cells (DCs), which express Toll-like receptors (TLRs) and secrete cytokines in response to encounter with microbes. Upon activation, NK cells directly lyse virus infected cells by exocytosis of granules that contain perforin and granzymes and secrete pro-inflammatory cytokines, such as IFN-γ and TNF-α, which mediate their immune response to infection (Carnaud 1999) {Siren, 2004 #123}{He, 2004 #125}.In this manner, NK cells function as important sentinels of the immune system, working as primary responders and alerting the host to the presence of infectious organisms. In a study investigating the importance of NK cells for protection against influenza A virus, contact between human NK cells and virus-infected macrophages induced NK cell-mediated IFN-γ production {Siren, 2004 #123}. In addition, gene transcription of IFN-γ and major MHC class I-related chain B (MICB), a ligand for the NKG2D receptor, by the NK cells was enhanced by virus-induced IFN-α. Importantly this study demonstrated interplay among type I and type II IFNs during influenza A virus infections

Figure 1.3. Cytokine interplay during influenza virus infection.

Influenza A virus is capable of infecting both epithelial cells and tissue macrophages. Epithelial cells produce RANTES, MCP-1, IL-8 and IFN-α/β, whereas macrophages produce a wider range of chemokines and cytokines as shown in the figure. Chemokines are involved in recruitment of leukocytes from the circulation to the site of infection. Cytokines IL-1b and TNF-α enhance the expression of cellular adhesion molecules, which contribute to enhanced leukocyte binding to endothelial cells. IFN-α/β, in addition to its antiviral effects, stimulates NK and T cell IFN-γ production in synergy with IL-18. IFN-g production is also enhanced by direct cellular interactions between NK or T cells and virus-infected cells. Based on references (Julkunen et al.,2000).

Antigen-presenting cells

The initiation and development of adaptive immune responses require that antigens be captured and displayed to specific cells. The cells that serve this pivotal role are called antigen-presenting cells (APCs). Exogenous viral antigens are taken up by APCs through endocytosis and provide a potential source of peptides that could bind to MHC Class I or II molecules in the APCs. The peptides are then presented to T lymphocytes by the APCs, effectively activating the adaptive immune response. These cells include macrophages and dendritic cells (DCs). Both macrophages and DCs share similar characteristics. They not only occupy a unique position as cells of the innate immune response and react to viruses via PRRs, they also scavenge dying cells and pathogens through phagocytosis and are potent releasers of type 1 IFNs and IL-1 β, important cytokines in bridging between the innate and adaptive immune systems (Gordon 2002). Despite having similar functions, macrophages are scavenging tissue-resident cells that mediate and amplify the innate inflammatory response by stimulating cytokine production by cells (Taylor 2005, Toews 1984), whereas DCs represent the true professional APC that trigger and regulate the adaptive immune response (Mellman 2001).

Role of alveolar macrophages

Macrophages mature and are derived from myeloid precursors called monocytes. Circulating monocytes migrate to tissues from the blood circulation in response to specific chemokines or tissue-specifc homing factors. In the lungs, alveolar macrophages (AMФ) are present in the interstitial tissues and the alveoli, residing at the interface between the air and lung tissue. As a result of their unique position in the lungs, AMФ provide the first line of host defense against a range of airborne pathogens, including influenza virus. It is the predominant APC population in the airways during steady state conditions {Chaudhuri, 2008 #114}. Characteristically, AMФ are thought to have a regulatory phenotype in the lungs, existing in a relatively quiescent state during homeostasis {Holt, 1978 #118}. These resting AMФ produce only low levels of inflammatory cytokines and are less phagocytic than their counterparts in other tissues {Holt, 1978 #118}. However, in the face of an influenza A virus infection, AMФ are able to mount potent antiviral immune responses. Following activation, AMФ convert into highly phagocytic cells that produce robust amounts of inflammatory cytokines, including IL-1β, IL-6 and TNF-α (Franke-Ullmann 1996) {Becker, 1991 #119} as well as a variety of inflammatory mediators such as chemokines, NO (Pendino 1993, Shellito 1995) and growth factors (e.g. GM-CSF and M-CSF) (Becker 1989). The AMФ in the lungs eventually become outnumbered and replaced by significant amounts of inflammatory mononuclear phagocyte subsets recruited via CCR2 {Dawson, 2000 #107}. These subsets differentiate into monocyte-derived DC (moDC) and inflammatory "exudate" macrophages {Lin, 2008 #108}{Perrone, 2008 #109}{Wareing, 2007 #110}{Wareing, 2007 #111}. While initially inflammatory cells during the course of infection, recent evidence suggests that these exudate macrophages will eventually develop into the suppressor phenotype of lung-resident AMФ and contribute to the lung resolution/repair phase. This not only helps to remove apoptotic/necrotic neutrophils, it also re-establish pre-infection homeostasis in the lungs over the course of a few days {Bilyk, 1993 #112}{Taut, 2008 #113}. The ability to recognize a wide range of endogenous and exogenous antigens is central to macrophage functions in homeostasis as well as in innate and acquired immunity.

Role of dendritic cells

Dendritic cells play an essential role in linking innate and adaptive immune responses. They not only express a wide array of PRRs and serve a direct role as effector cells in the innate immune responses to infection; they also play a crucial role in inducing adaptive immune responses by processing and displaying antigen to naïve T cells. DCs derive from hematopoietic bone marrow precursor cells and belong to a distinct lineage of hematopoietic mononuclear cells. These progenitor cells initially transform into immature dendritic cells that are characterized by their high endocytic activity and low T-cell activation potential. The immature DCs residing within secondary lymphoid organs (e.g. the spleen and lymph nodes) and at peripheral sites/body surfaces (e.g the gastrointestinal tract, the genitourinary tract, and the respiratory tract) constantly sample the surrounding environment for pathogenic stimuli. They express PRRs (TLRs, NLRs and C-type lectins) which recognize pathogenic antigens called PAMPs (Iwasaki 2004, Marshak-Rothstein 2006, Meylan 2006, Figdor 2002). Once stimulated by PAMPs, DCs migrate to the local lymph nodes, where they mature and develop the capacity to capture, process and present the antigen to drive an adaptive T cell response. Simultaneously, they also express high levels of MHC and T-cell co-stimulatory molecules such as CD80, CD86, and CD40, greatly enhancing their ability to activate T-cells (Wilson 2005, Legge 2003, Belz 2004). They also upregulate CCR7, a chemotactic receptor that induces the dendritic cell to travel through the blood stream to the spleen or lymph nodes. Depending on the type and dose of antigen, the DC subset, and the regional cytokine microenvironment, different effector T cells are generated

The respiratory tract (RT) is a major site of antigen encounters with DCs. Like DCs isolated from secondary lymphoid organs and/or in peripheral tissues (Henri 2001, Villadangos 2005), the non inflamed respiratory tract DCs (RDCs) are composed of several cell subsets that are heterogeneous in phenotype (Lambrecht 2003, von Garnier 2005, Sung 2006, Wikstrom 2007). The subsets are defined based largely on the differential expression of specific cell surface markers, and also on the anatomic distribution of the particular DC subset (von Garnier 2005). RDCs express varying levels of CD11c and CD11b and in addition, further levels of heterogeneity exist for expression of MHC class II, CD80, CD86, Gr-1 and B220, as well as functional and regional heterogeneity (Legge 2003). Recent studies have shown that different RDC subsets also perform different functions, and have different roles in inducing T cell responses (Sung 2006, del Rio 2007, Beaty 2007) with some subsets of DCs being better at cross-presentation of antigen to CD8 cells on MHCI molecules and others better at presenting endocytosed antigen to CD4 T cells on MHCII molecules (Banchereau 1998, Villadangos 2007). RDCs are distributed throughout the whole lung and can be found in every compartment including both large extrathoracic- and intrathoracic-conducting airways, the visceral pleura, the perivascular space, as well marginating inside the pulmonary lung vessels. They are also found throughout the lung parenchyma which is accessible by lung tissue digestion and the alveolar compartment, accessible by bronchoalveolar lavage (Sertl 1986, Gong 1992, Holt 1994, Pollard 1990, Nelson 1994, Suda 1998). The phenotypic characteristics of RDCs are further described in the sections below.

DC type

Mouse (see ref below)

Conventional DC

(cDCs)

CD11c+, MHCII+, Mac-1+

Plasmacytoid DC

(pDCs)

CD11clow, MHCIIlow, Mac-1-, 120G8+, Gr-1 (Ly6G/C)+, B220+

Table 1.4 Respiratory tract DC described in the mouse lung

(von Garnier 2005, de Heer 2004, Byersdorfer 2001, Wikstrom 2006, Wikstrom 2007, de Heer 2005)

Conducting airway DCs form a dense, highly dendritic and well-developed intraepithelial network that project into the airway lumen for sampling of environmental antigens, even in steady state conditions. They are located above and beneath the basement membrane, are mainly of the myeloid origin and show a high turnover of about 2-3 days (Holt 1994, Lambrecht 1998). Conducting airways DCs have two resident populations. The CD11chi MHCIIhi CD11bneg subset resembles Langerhans cells and has been shown to express langerin and the mucosal integrin CD103 (GeurtsvanKessel 2008, Sung 2006). In addition, these cells also extend their dendrites between bronchial epithelial cells into the lumen and this provides continuous surveillance of the airway lumen (GeurtsvanKessel 2008, Jahnsen 2006, Lambrecht 1998, Sung 2006). Immediately below, the submucosa of the conducting airways contains CD11chi MHCIIhi CD103- cells that express high levels of CD11b. These cells are a rich source of proinflammatory chemokines (Sung 2006, van Rijt 2005) and are particular suited for priming and restimulating effect CD4+ T cells in the lungs (van Rijt 2005, del Rio 2007). These DCs do not express CD8α, a marker present on a subset of lymphoid organ DCs, or the pDC marker Gr-1 (Vermaelen 2004).

Interstitial lung DCs are found in the lung interstitium, which is defined as the space in between alveolar epithelial cells and alveolar capillaries. The phenotype and function of interstitial lung DCs can be assessed by enzymatic digestion of peripheral lung lobe and they generally have a much longer half life of about 10 days (GeurtsvanKessel 2008, von Garnier 2005, Holt 1994). In mice, interstitial DCs are predominantly CD11c+ and like conducting airway DCs, can also be further divided into CD11b+ and CD11b- subsets (GeurtsvanKessel 2008, von Garnier 2005). They are also immature as assessed by the low expression of the costimulatory molecules CD40, CD80, CD86 (Huh 2003,Vermaelen 2004, de Heer 2004,Stumbles 1998, van Rijt 2005, Vermaelen 2004).

Alveolar DCs are present in the alveolar space and is easily accessible by bronchoalveolar lavage. The alveolar compartment also contains autofluorescent alveolar macrophages that can be easily confused with alveolar DCs if one does not take autofluorescence into account (Vermaelen 2004). In mice, alveolar DCs are low aotuofluorescent cells that are positive for F4/80, CD11b and CD11c. In steady state, these cells comprise a minor portion of respiratory dendritic cells, but they expand considerably in the lungs when inflammation is induced (Julia 2002).

Plasmacytoid DCs are also found in the conducting airways and the interstitial compartments with a slight preference for the latter. They are CD11cint cells that also express the bone-marrow stromal antigen-1 (recognized by monoclonal antibodies 120G8 and mPDCA-1), Siglec-H, and some markers shared with granulocytes and B cells, Ly6C and B220 (De Heer 2004, GeurtsvanKessel 2008, Kool 2009). In the steady state, they represent only a minor population of respiratory DCs. pDCs express TLR-7 and -9, TLRs that detect the presence of DNA and RNA viruses and hence, are able to play an important role in influencing the initial innate immune response to viral infection (Kadowaki 2007, Jarrossay 2001). Upon viral infection, they are able to quickly secrete large amounts of type I IFNS that increase NK cell cytotoxity and induce effector T cell functions (Siegal 1999, Agnello 2003, Krug 2004). Moreover, it has been demonstrated that type I IFNs in turn, also promote differentiation and maturation of monoytes into short lived DCs (Santini 2000). In addition, pDCs have also been shown to produce IL-1 and IL-6 to induce human B cell differentiation into antibody producing plasma cells (Jego 2003).

Under inflammatory conditions, such as viral and bacterial infections, toll like receptor ligands and environmental allergens, chemokines are produced that attract monocytes and inflammatory cells to the lungs (GeurtsvanKessel 2008, McGill 2008). These monocytes are believed to be the immediate precursors to the inflammatory CD11b+ monocyte-derived DCs that rapidly upregulate CD11c. They also retain expresson of Ly6C as a remnant of their monocytic descent (GeurtsvanKessel 2008, Hammad 2009, Jakubzicket 2008). Under some conditions, inflammatory cells can also nitric oxide synthase and are so called tumor necrosis-factor-producing inducible nitric oxide synthase producing DCs (Serbina 2003, Wang 2006). Inflammatory DCs can also be easily confused with resident CD11b+ cDCs (Grayson 2007).

Figure 1.5. Dendritic cell subsets in the lung

The conducting airways are composed of airway epithelial cells, which act as a molecular sieve excluding inhaled antigens and pathogens molecular patterns (PAMPs).

Cells of the adaptive immune response

There are two types of adaptive immune responses, humoral immunity and cell-mediated immunity that are mediated by different components of the immune system and function to eliminate different type of pathogens. Humoral immunity is mediated by the production and secretion of antigen specific antibodies produced by B cells whereas cell-mediated immunity is mediated by mainly T cells, requiring the help of antigen presenting cells.

B cell antibody responses

B cell responses and virus-specific antibodies play a pivotal role in primary influenza viral clearance (Gerhard 2001). The main function of a B cell is to make antigen-specific antibodies. Neutralizing virus-specific antibodies are usually directed against the two major viral proteins, the HA, the NA as well as the matrix (M) 2 protein, all of which can be found on the external surface of the virion (Epstein 1993, Neirynck 1999). The importance of the humoral response has been demonstrated in several studies using mice lacking in B cells (μMT mice). Although early virus control was not impaired, the mice failed to clear the virus and eventually succumbed to infection (Graham 1997, Lee 2005). In addition, they were also particularly susceptible to small doses of the A/PR/8 virus but could clear the less pathogenic HKx31 virus with normal effector T cell responses (Topham 1996, Gerhard 1997, Mozdzanowska 1997). Taken together, the above data suggests that the contribution that B cells make to viral clearance may depend on the virulence and pathogenicity of the viral strain (Bender 1992, Graham 1997).

Naïve B cells can be activated in a T-cell dependent or independent manner. A T-cell dependent response requires recognition of antigen by helper CD4+ T cells and direct contact between the CD4+ helper T cells and the antigen specific B cell. In this response, naïve CD4 T cells that have been activated by costimulation and antigen, express the CD40 ligand that interacts with the CD40 receptor on B cells that are activated by the same antigen. This CD40L-CD40 interaction, in addition to the interaction between CD4+ helper T cells and B cells and cytokine signaling, drives B cell proliferation and differentiation into antigen-specific antibody secreting cells and memory B cells (Bishop 2001). Helper T-cell dependent responses induce isotype switching in B cells, leading to the production of antibodies that consist of different immunoglobulin (Ig) isotypes. Different isotypes mediate different effector functions (Bishop 2001). It is the production of these isotype-switched, virus-specific antibodies during the later stages of the primary response that is required for optimal virus clearance and antibody-mediated protection (Palladino 1995). In a T-cell independent manner, a humoral response is induced without the involvement of helper T cells. T-independent antigens are non-protein antigens such as polysaccharides, glycolipids and nucleic acids. These antigens cannot be recognized by helper T cells as they are not processed and presented as MHC molecules. Most TI antigens are composed of multiple identical epitopes. Hence, B cell activation can be achieved through polyclonal activation which involves the cross linking of antigen molecules on a B cells. Antibody responses to T-cell independent antigens consist mainly of low affinity IgM and IgG. Activated B cells not only produce antibodies; they also secrete various cytokines (Liles 1995), are strong stimulators particularly for CD4 T cells (Krieger 1985) and could contribute to recovery by any one of these functions.

Following virus clearance, influenza-specific B cell subsets that are formed in the secondary lymphoid organs migrate to the lymphoid and non lymphoid tissues where they reside throughout the life of the host. B cell memory subsets are divided into two populations, the long-lived plasma cells and memory B cells both of which are generated by contact dependent T-B cell interactions and CD40 signaling in the germinal centre (McHeyzer 2005, Bachmann 1994, Silfka 1998, Noelle 1992, Lee 2003). The long-lived plasma cells are antibody secreting cells. Following viral clearance, the plasma cells migrate out of the germinal centre and localize to the bone marrow where they continue to produce antibodies even when the antigen has been eliminated (Slifka 1996). In contrast, memory B cells are widely dispersed to many tissues. They persist in a quiescent state and require stimulation to divide and differentiate into antibody secreting cells. Upon encounter with recall antigen, memory B cells are able to generate a rapid, vigorous, and high-affinity secondary antibody response (Bachmann 1994, Slifka 1998). Interestingly, these cells localize at a higher frequency in the lung tissue following influenza virus infection, suggesting that the nature of the infection may alter the migratory capacity of these cells (Joo 2008). Although it is unclear whether specific adhesion molecules or chemokine receptors play a role in the tissue-specific migration of memory B cells, the localization of these cells to the lung would allow them to rapidly recognize and respond to a secondary influenza virus challenge.

T cells and the response to influenza

T cells play a crucial role in initiating the adaptive immune responses. Prior to antigen contact, naïve T cells preferentially home to and re-circulate through the peripheral lymphoid tissues (spleen, lymph nodes and Peyer's Patches) via the blood and lymph. Within the T cell areas of the lymphoid tissues, APCs present antigenic peptides in the context of MHC to passing naïve T cells, effectively initiating the immune responses. Naïve T cells that receive the appropriate antigenic and co-stimulatory signals by APCs are activated and stimulated to clonally expand into antigen-specific effector T cells, some of which may leave the lymphoid organs and re-distribute into peripheral sites of infection and/or inflammation to remove infected cells. In the effector phase of the response, the CD8+ cytotoxic T lymphocytes (CTLs), the effector cells of the CD8+ subset respond by killing infected cells via direct cell-cell contact. Much of the present knowledge on murine CD8+ T cell immunity to influenza is based on mice infection models using the mouse adapted influenza strains of HKx31 (X31, H3N2) and A/PR/8/34 (PR8, H1N1). The role that virus-specific CD8+ T cells play in resolving respiratory virus infections has been emphasized in a number of studies where CD8+ T cell deficient mice have shown delayed virus clearance (Hou 1992, Eichelberger 1991; Bender 1992). Moreover, in mice lacking B cells or neutralizing antibodies, CD8+ T cells were also able to provide significant immunity against viral infections (Graham 1997, Epstein 1998). Virus-specific CD4+ T cells are also important for viral clearance. They not only produce cytokines that activate (help) macrophages and B lymphocytes, they also play a significant role in augmenting CD8+ T cell responses (Doherty 1997, Mozdzanowska 1997). In mice lacking CD8+ T cells or B cells, monoclonal antibody depletion of CD4+ T cells worsened viral infection and delayed virus clearance (Eichelberger 1991, Mozdzanowska 1997, Topham & Doherty, 1998). More importantly, depletion of CD4+ T cells in mice also decreased recruitment of CD8+ T cells to the infected lungs, resulting in delayed viral clearance (Mozdzanowska 2000).

In general, T cell responses to the influenza A virus are limited to the lung epithelium as viral replication is usually confined to this site (Walker 1994, Walker 1992). Upon viral exposure, activated mature DCs lining the epithelium begin to migrate to the local lymph nodes (mediastinal and cervical) where they prime naïve CD8+ and CD4+ T cells (Harmsen 1985, Vermaelen 2001). At the same time, chemokines in the lungs begin to change the integrin affinity to allow for efficient extravastion and trafficking of T cells to the site of infection. (Constantin 2000, Thatte 2003, Dawson 2000,Sallusto 2000). Following T cell receptor engagement, the naïve T cells undergo a programme of activation, differentiation and expansion in the local lymph nodes 3-4 days after infection (Lawrence 2004, Tripp 1995). The virus-specific T cells than migrate to the lungs and localize to the infected epithelium where they mediate their antiviral activities (Bender 1992, Cerwenka 1999, Doherty 1996, Flynn 1998, Legge and Brachiale 2003, Norbury 2002, Topham 1997, Woodland 2001). Virus-specific CD8+ T cells usually appear in the lung airways and lung parechyma 5-7 days after infection (Lawrence 2005) and they exert their effector functions by secreting antiviral cytokines and lysing infected epithelial cells that express the specific viral antigens (Hou 1992, Roman 2002). The virus specific CD4+ and CD8+ effector T cells in the lung predominantly produce IFN-γ and TNF-α (Carding 1993, Mayer 2005). In addition, CD8+ effector T cells mediate apoptosis of infected epithelial cells via Fas-FasL interactions or the exocytosis of cytolytic granules containing perforin and granzymes (Predergast 1992, Hou 1995, Topham 1997). While the CD4+ T cell subset is not required for efficient clearance of influenza A virus from the lung, optimal CD8+ T cell expansion and responses appear to depend on CD4+ T cells (Allan 1990, Tripp 1995, Belz 2002, Eichelberger 1991, Hou 1992). Through the combined abilities of the effector T cells to secrete inflammatory cytokines and kill infected cells, a typical acute viral infection can be resolved within days. Under normal circumstances, the virus is normally eliminated by day ten following primary influenza infection and coincides with the peak of the CD8+ T cell response (Eichelberger 1991, Doherty & Christensen, 2000). Following antigen clearance, the CD8+ T cell response is down regulated and the majority of the antigen-activated effector T cells die by apoptosis. Only a small fraction survives and differentiates into long-lived antigen-specific memory T cells that persist for the life of the host (Belz 2000, Hogan 2001, Marshall 2001).

The memory T cell compartment is heterogeneous in terms of development, effector functions, surface phenotype and homing properties (Sallusto 2004, Sallusto 1999, Willinger 2005, Woodland and Dutton 2003). Many of these memory CD4 and CD8 T cells can be found in various anatomical compartments such as the spleen, lymph nodes, lungs and also in non-lymphoid organs such as live and bone marrow (Hogan 2001, Marshall 2001, Masopust 2001). This has led to the classification of memory T cells into two subsets based on their preferential migration. The 'effector' memory T cells (TEM) represent a pool of antigen primed cells which migrate primarily to the non-lymphoid organs (i.e. lungs and liver) where they provide a first line of defence against invasive pathogens. These highly activated cells are involved in immediate protection and are capable of immediate effector function upon antigen encounter (Masopust 2001, Sallusto 1999). In contrast, the 'central' memory T cells (TCM) subset consists of a long-lived clonally expanded antigen-primed population of memory cells which resides in the peripheral lymphoid organs. They are involved in secondary responses and long-term protection, and upon re-infection, readily proliferate and differentiate into effector cells (Arbones 1994, Cyster 2000, Rosen 2004, Sallusto 2004, Wherry 2003, Woodland and Dutton 2003). The extent in which the different subsets contribute to controlling viral infections are not clear. Upon re-exposure to the same antigen, these memory T cells are capable of rapid proliferation and generating new effector T cells that are responsible for the enhanced secondary immune responses (Eichelberger 1991, Flynn 1998, Graham and Brachiale 1997, Hou 1992). This sustained recall response to the infection occurs earlier and is of a greater magnitude than the primary response (Hogan 2001, Liang 1994, Ely 2003 CE, Roberts 2005). In the case of influenza virus infections, it has been clearly established that both CD4+ and CD8+ memory T-cell subsets respond to, and mediate substantial control of, a secondary virus infection (Flynn 1999, Flynn 1998, Liang 1994, Yap 1978 Cauley 2002, Novak 1999). This is in contrast to the primary response, during which viral clearance depends primarily on CD8+ T cells (Eichelberger 1991, Hou 1992, Epstein 1998, Doherty 1992, Benton 2001). Importantly, memory CD4+ T cells directly mediate antiviral activity through an IFNγ-dependent mechanism (Zhong 2001, Zhong 2000). Although virus-specific memory CD4+ and CD8+ T cells are not able to prevent respiratory infections per se, they can reduce the maximal viral load in the lung, mediate accelerated viral clearance (usually by several days), and protect against death following challenge with a lethal dose of virus in animal models (Liang 1994, Flynn 1998, Nguyen 1999, Anker 1978). As might be anticipated, the level of protection appears to depend on the magnitude of the CD8+ T-cell response (Christensen 2001). Adapted from Gerhard et al, Table 1.4 illustrates the complex interplay that cells of the adaptive immune response play in viral clearance (Gerhard 2001). Removal of a virulent strain of influenza requires a combination of cytotoxic CD8+ T cells, cytokine secreting CD4+ helper T cells and antibody secreting B cells.

CD8 T cells

CD4 T cells

B cells

Clearance (days)

Survival (%)

+

+

+

7-10

100

-

+

+

10-14

100

-

+

-

>20

0

-

-

+

>20

0

+

-

-

>14

20

+

+

-

10-14

35-85

+

-

+

10-14

90

-

-

-

>20

0

Table 1.5. Table demonstrating the complexity of the immune responses to virulent strains of influenza

Using antibody treatment, genetically altered mice or a combination of both, cells of the adaptive immune response were individually depleted to demonstrate the interaction between the cells. As shown in rows 3, 4 and 5, neither CD8+ T cells, CD4+ T cells nor B cells alone can effectively clear virus or promote survival of mice given a sublethal dose of A/Puerto Rico/8/34. Delayed kinetics and increased survival occurs with a combination of cells, suggesting an interaction between adaptive immune cells is required for viral clearance.

Tyrosine kinase signaling in anti-viral responses

During an inflammatory response, immune cells must be able to communicate with one another so as to establish a state whereby the organism as a whole is able to identify and kill the pathogen. To survive this challenge, multiple mechanisms have evolved to protect the host against such infections. Such communication mechanisms depend heavily on extracellular signaling molecules such as cytokines and chemokines, antibodies, and reactive oxygen species. At a cellular level, these molecules bind to receptors on the surface of immune cells, thereby activating a series of intracellular signaling pathways necessary for removing the pathogen (Schlessinger 2000). The majority of intracellular signaling pathways are highly regulated by protein kinase activity, and in the human/mouse genome, there are over 500 families of protein kinases that fall into various subfamilies based on their structure and function (Manning 2002). The Src family of protein tyrosine kinases (SFKs) was first identified as a proto-oncogene and are proteins that possess biochemical kinase activity essential for intracellular single transduction (Hunter 1980). Since their discovery, the intracellular signalling cascades involving the SFKs have been extensively studied (Frame 2002, Parsons 2004, Chong 2005).

Writing Services

Essay Writing
Service

Find out how the very best essay writing service can help you accomplish more and achieve higher marks today.

Assignment Writing Service

From complicated assignments to tricky tasks, our experts can tackle virtually any question thrown at them.

Dissertation Writing Service

A dissertation (also known as a thesis or research project) is probably the most important piece of work for any student! From full dissertations to individual chapters, we’re on hand to support you.

Coursework Writing Service

Our expert qualified writers can help you get your coursework right first time, every time.

Dissertation Proposal Service

The first step to completing a dissertation is to create a proposal that talks about what you wish to do. Our experts can design suitable methodologies - perfect to help you get started with a dissertation.

Report Writing
Service

Reports for any audience. Perfectly structured, professionally written, and tailored to suit your exact requirements.

Essay Skeleton Answer Service

If you’re just looking for some help to get started on an essay, our outline service provides you with a perfect essay plan.

Marking & Proofreading Service

Not sure if your work is hitting the mark? Struggling to get feedback from your lecturer? Our premium marking service was created just for you - get the feedback you deserve now.

Exam Revision
Service

Exams can be one of the most stressful experiences you’ll ever have! Revision is key, and we’re here to help. With custom created revision notes and exam answers, you’ll never feel underprepared again.