Innate and adaptive immune response to virus

Abstract

The host counters a viral infection through a complex response made up of components belonging to both the innate and the adaptive immune system. In this report, we review the mechanisms underlying this response, how it is induced and how it is co-ordinated. As cell-cell communication represents the very essence of immune system physiology, a key to a rapid, efficient and optimally regulated immune response is the ability of the involved cells to rapidly shift between a stationary and a mobile state, combined with stringent regulation of cell migration during the mobile state. Through the co-ordinated recruitment of different cell types intended to work in concert, cellular co-operation is optimized particularly under conditions that may involve rare cells. Consequently, a major focus is placed on presenting an overview of the co-operative events and the associated cell migration, which is essential in mounting an efficient host response and co-ordinating innate and adaptive immunity during a primary viral infection.

Introduction

Viruses are infectious pathogens that exploit the host's cellular machinery for their survival and replication. The host defence against viral infection consists of a complex interplay between components of the innate and the adaptive immune system. The innate immune response represents a rapid first line of defence, but it is often insufficient by itself to clear or permanently control a viral infection. However, innate immune mediators play a very important role in keeping the virus load low until a specific, adaptive immune response can be generated. Equally important, components of the innate response shape the adaptive immune response and direct the subsequent effector phase. Indeed, it is justified to state that an appropriate innate response is the foundation upon which host survival depends.

The innate immune system comprises several cell types, including dendritic cells (DCs), monocytes/macrophages and natural killer (NK) cells, which, besides constraining the virus spread and eliminating virus‐infected cells, secrete high levels of proinflammatory cytokines and chemokines, which direct not only the activation and differentiation of the adaptive immune response but also the subsequent recruitment of antigen‐primed effector T cells to the sites of viral replication. The adaptive immune response towards viruses is mediated by T and B cells expressing clonally distributed, antigen‐specific receptors. T and B cells are activated and differentiate in the secondary lymphoid organs (SLO) through an interplay between several cell types of both the innate and the adaptive immune system including professional antigen‐presenting cells (APC). DCs are a specialized family of APCs that effectively link innate recognition of invading pathogens to the generation of the appropriate type of adaptive immune response . During viral infection, they play a key role in sensing and processing viral information and directing the differentiation of naïve T and B cells to virus‐specific effector T cells and antibody‐secreting plasma cells. Although other cell types, such as macrophages or activated parenchymal cells, may serve as APCs activating primed T cells, DCs are probably the only class of APCs that effectively activate naïve T cells. DCs reside in essentially any tissue in an immature form, and during viral infection they become activated either upon a direct viral encounter or through interaction with other local cells of the innate immune system secreting cytokines and chemokines. Following activation in a peripheral site, the activated DCs migrate towards the regional draining lymph nodes by means of the afferent lymphatics. In the SLO, antigen is presented by professional APCs to rare antigen‐specific T and B cells that eventually become activated; subsequently, these may interact to regulate the induced adaptive responses, e.g. the generation of a T helper cell‐dependent antibody response. While antibodies are rapidly distributed throughout the accessible fluid phase of the host, T cells require close contact with APCs to perform their effector function. Once activated, T cells are therefore released into the blood stream, and from the circulation activated T cells are directed to areas of inflammation to exert their antiviral effector function.

From the above brief description of how the immune response unfolds during a primary viral infection, it is immediately evident that mechanisms controlling leucocyte mobility and migration play a key role in deciding the efficiency of the induced immune response. For this reason, the study of factors regulating the expression of adhesion molecules and their interaction with matching ligands has become a central area of research in infection immunology. While the expression of adhesion molecules – in particular members of the integrin family e.g. LFA‐1 and VLA‐4 – on the leucocyte surface is determined by their type and state of differentiation, the expression of relevant vascular ligands and the affinity between the two is strongly influenced by local signals present in the involved tissue. Thus, cytokines control the state of endothelial activation and in this manner the expression of relevant ligands for the adhesion molecules expressed by circulating leucocytes.

Chemokines, on the other hand, regulate the affinity of integrin binding to their matching ligands of the immunoglobulin (Ig) superfamily (ICAM‐1 and VCAM‐1) expressed by activated endothelium. In this manner, these secreted mediators regulate which cells are recruited to which sites, e.g. the draining lymph nodes, sites of inflammation and/or other relevant tissues in the host. Importantly, the local production of cytokines and chemokines is strongly influenced by cells of the innate immune system such as neutrophils, monocytes/macrophages, DCs and NK cells. An optimal activation of the innate immune system is therefore believed to be important not only for the generation of the antigen‐specific effector cells but also in shaping the inflammatory exudate, which represents the foundation for efficient elimination of most invading pathogens as well as any associated immunopathology. 

 

Fig. 2. Antiviral host response

Innate immune response to Virus

Many cell types, but in particular cells of the innate immune system, express germline‐encoded pattern recognition receptors (PRRs) that detect invariant molecular structures (pathogen‐associated molecular patterns, PAMPs) shared by all pathogens of a given class, e.g. all RNA viruses. With regard to viral infections, nucleic acid‐ and glycoprotein‐PAMPs act on distinct classes of PRRs, which include certain Toll‐like receptors (TLRs 2, 3, 7–9 and perhaps 4), retinoic acid inducible gene‐I, melanoma differentiation‐associated gene 5, dsRNA‐dependent protein kinase  and the DNA receptor DAI. These PRRs differ in their cellular localization, ligand specificity and downstream signalling pathways, creating a situation where multiple sensor systems have the opportunity to be involved in the detection of any viral infection of the host. Upon sensing the invading viral pathogen through the appropriate PRR(s), multiple distinct signalling pathways become activated; for viruses key molecules are transcription factors such as interferon regulatory factor (IRF) 3 and 7 as well as nuclear factor κB (NF‐κB). For a more detailed overview of PRRs and their signalling pathways, we refer the reader to the accompanying review from the group of S. R. Paludan. Activation of these pathways leads to a marked reprogramming of the gene expression profile of the cell sensing the infection and the activation of a wide variety of genes playing a key role in the innate host defence against viral infection. Thus, the downstream effects of PRRs signalling include the secretion of proinflammatory cytokines and chemokines co‐ordinating innate and adaptive immunity. Some of the most critical mediators in the innate host response to viral infection are the type I interferons (e.g. IFN‐α and IFN‐β). Type I IFNs in turn induce the expression of hundreds of IFN‐stimulated genes that may have direct antiviral activity and/or modulate innate and adaptive immunity by activating immature DCs, enhancing NK‐cell function  and promoting survival and effector functions of T and B cells.

Role of cytokines and chemokines

As mentioned above, multiple cytokines and chemokines are released during viral infection as a consequence of PRR signalling in cells such as epithelial cells, macrophages and DCs. The major inflammatory cytokines of the innate response induced by a viral infection include TNF‐α, type I IFNs, IL‐1, IL‐6, IL‐12 and IL‐18, where type I IFNs represent key contributors to the activation of innate and adaptive immunity during viral infection. Unlike type II IFN (IFN‐γ), which is produced predominantly by primed T cells and activated NK cells, type I IFNs can essentially be produced by any nucleated cell in response to viral infection, and all cells can respond to type I IFNs through the type I IFN receptor (IFNAR), which binds all type I IFN subtypes. However, not all cell types are equally important in generating an optimal type I IFN response. Thus, it has recently been found that production of type I IFN from bone marrow‐derived cell types – as opposed to parenchymal cells – was essential for the early control of virus replication in several different models of systemic viral infection, strongly indicating that cells of bone marrow origin are more critical than other cell populations (regarding this point, see further below). As briefly mentioned, type I IFNs are induced by the transcription factors IRF3 and IRF7.

While IFN‐β production may be induced by IRF3 homodimers alone, the production of IFN‐α via both cytosolic and transmembrane PRR pathways requires the expression of IRF7, either as homodimers or as heterodimers with IRF3. For this reason, IRF7 has been called the master regulator of the type I IFN response. IFN‐α/β works in an auto and paracrine fashion, leading to amplification of the original signal, which in turn induces a heightened antiviral state. Thus, initially IRF3 and 7 induce small amounts of IFN‐β/‐α (and other cytokines and chemokines), resulting in type I IFN signalling via the IFNAR. This induces a marked up‐regulation of IRF7, leading to full expression of the available type I IFN genes. The end result is secretion of high levels of cytokines and chemokines, which recruit cells of the innate immune system including monocytes and NK cells to local virus‐infected tissues, stimulate NK‐cell activation, induce an antiviral state in neighbouring cells, amplify DC activation and differentiation and in turn facilitate the induction of the adaptive immune response.

Interestingly, it was recently shown that local production of IFN‐β in the central nervous system suppresses experimental autoimmune encephalomyelitis by inhibiting the expression of certain chemokines and modulating antigen processing and presentation in microglia and macrophages. This might be an endogenous protective mechanism that is elicited upon inflammation of the brain only, an organ that cannot tolerate inflammation well compared with other organs. Another explanation might be that IFN‐β initially works in a proinflammatory manner, amplifying the early host response, and then later plays an anti‐inflammatory role to prevent an overreaction by the adaptive immune system.

Dcs

DCs provide an important interface between innate and adaptive immunity. There are two major DC subsets, which fulfil different, non‐redundant tasks in the formation of the antiviral host response.

One major DC subset that is particularly important during viral infection is plasmacytoid DCs (pDCs). These cells circulate through blood and lymphoid tissues, and compose a specialized subset of DCs characterized by their ability to produce large amounts of type I IFNs. Thus, in response to many viruses, pDCs may produce 10‐ to 100‐fold more type I IFN on a per cell basis compared with other cell types, including other types of DCs and macrophages. Accordingly, pDCs have been shown to release the first wave of type I IFNs and may therefore support subsequent steps of antiviral immunity including NK‐cell activation and T‐cell differentiation in the context of many viral infections. Moreover, experimental evidence suggests that pDCs may be recruited to inflammatory sites and draining LNs, and in this manner become a potent local source of type I IFNs. However, other cell types such as other types of DCs and macrophages may also significantly contribute to type I IFN production during viral infection despite their lower per‐cell production capacity for type I IFNs.

In contrast to their central role in type I IFN secretion, most studies indicate that pDC are rather inefficient in presenting antigen to naïve T cells, even though they, to a certain degree, may be able to activate naïve T cells and induce these to transform into effector cells. Thus, initial priming of T cells responses in many viral infections relies predominantly on other types of DCs. Indeed, it was recently reported that pDCs, activated through TLRs, can induce regulatory T cells, which in turn may inhibit the expansion of Ag‐primed T cells and thus prevent overstimulation of the adaptive immune system. However, in the context of viral infection, pDCs have also recently been found to improve antigen presentation by restoring the activity and communication of virally perturbed LN–DC networks.

Monocyte/macrophages

Monocyte/macrophages may play a role in relation to the control of viral infection in two different ways. First, resident macrophages may constitute an important first line of defence, together with proinflammatory cytokines and chemokines. Second, as a result of the induced local inflammatory response additional macrophages are recruited as a result of transformation of blood‐borne monocytes, which are attracted to the inflammatory site particularly through their expression of CCR2; these inflammatory macrophages may be important during the induced innate phase as well as during the adaptive phase of the host response.

Resident macrophages are ubiquitous cells strategically placed to act as a first line of defence by their position near normal portals of viral entry, in LNs and in close contact with circulating blood. A number of viral models have provided convincing evidence that macrophages play a key role in many cases of genetically determined innate resistance to viral infection. One mechanism of how this may work is that macrophages may be resistant or at least less permissive than other cell types to viral replication (intrinsic antiviral activity).

Interestingly, some observations indicate that the initial level of resistance may be regulated by low‐grade ‘spontaneous’ production of type I IFNs. Additionally, macrophages are themselves potent producers of a range of cytokines including type I IFNs and the release of soluble mediators may in fact be the most important function during the early response to viral infection.

Finally, resident macrophages line the sinuses of the SLO, where they capture small microorganisms and particulate antigen. These sinuses are also transit zones for pathogen‐loaded DCs, and this anatomical co‐localization provides the physical basis for the optimal funnelling of a wide range of antigens into the zones of antigen presentation within the SLO.

The role of inflammatory macrophages in the host response to viral infection is less well explored; however, there are several instances in the literature where prevention of this second wave of macrophage involvement has been found to markedly affect the outcome of viral infection. Inflammatory macrophages may also play a key role in the induced innate response. Thus, during cytomegalovirus infection of the murine liver, resident macrophages respond to type I IFN by up‐regulation of CCL2, which in turn recruits CCR2‐expressing inflammatory macrophages; the latter secrete high amounts of CCL3, which attracts CCR5‐expressing NK cells, a key population in controlling early viral replication in this infection model.

NK cells

NK cells are another innate effector cell type that influences the shape of both the innate and the adaptive immune response during viral infection. NK cells constitutively express transcripts for certain inflammatory cytokines, e.g. IFN‐γ, and they contain preformed intracellular granules storing cytolytic mediators such as perforin and granzymes. The effector functions of activated NK cells therefore include lysis of virus‐infected cells and the secretion of proinflammatory cytokines (e.g. IFN‐γ, TNF‐α and GM‐CSF) and chemokines (e.g. CCL4 and CCL5). Through their soluble mediators, NK cells may themselves augment the local innate inflammatory response. For example, in the case of murine cytomegalovirus infection, it has been found that NK‐cell production of IFN‐γ may be essential to the local secretion of CXCL10 in the liver. As mentioned above, the NK cells themselves are attracted to the virus‐infected liver through CCL3 produced by recently recruited inflammatory macrophages.

NK cells are primarily activated by type I IFNs or proinflammatory cytokines such as IL‐12, IL‐15 and IL‐18, where DCs are the main source of these cytokines. Notably, different cytokines induce different aspects of DC‐induced NK‐cell activation and steer the innate immune response to distinct NK‐cell effector functions. Thus, IL‐12 primarily induces IFN‐γ secretion by NK cells, while type I IFNs enhance NK cell‐mediated cytotoxicity, and IL‐15 has the capacity to trigger NK‐cell proliferation and survival. Interestingly, different DC subsets are known to differ in their capacity to produce these cytokines. Thus, based on their superior ability to produce type I IFNs, pDCs mainly enhance NK‐cell cytotoxicity, whereas conventional (myeloid) DCs mainly stimulate IFN‐γ production and proliferation by NK cells. Finally, some of these cytokines may trigger the whole spectrum of NK‐cell activities, provided they are present in high enough concentrations. In turn, IFN‐γ and TNF‐α produced by NK cells can also affect the maturation and effector function of neighbouring DCs (up‐regulation of co‐stimulatory molecules and secretion of cytokines) as well as other leucocytes, including macrophages, granulocytes and other lymphocytes, which are recruited as a consequence of viral infection.

NK cells may also be activated through direct recognition of virus‐infected host cells. This is due to their expression of a sophisticated repertoire of receptors including NKG2D, which recognize an array of cellular stress‐induced molecules. Through these receptors, NK cells are able to distinguish between uninfected, normal cells and stressed, infected cells. According to the missing self‐hypothesis, NK cells may also be activated by the loss of MHC expression on some infected cells. A set of inhibitory receptors normally recognize MHC class I and block target cell killing, but if the signal from these receptors is too weak, degranulation and cell killing can be induced. In this manner, NK cells complement the CD8⁺ T cells, and viruses trying to avoid CD8⁺ T cell‐mediated killing through down‐regulation of MHC class I may still be targeted by the host response. In addition, NK cells express activating immunoglobulin natural cytotoxicity receptors including CD16, which mediate antibody‐dependent cellular cytotoxicity, eliminating virus‐infected cells coated with specific IgG. Direct contact with the infected cells is not, however, absolutely required for the NK cells to participate in the antiviral host response, because they can be activated simply by exposure to IFNs and other cytokines in their environment. Finally, NK cells have also been shown to express TLR3 and 9, but it is not known whether NK‐cell activation through ligation of these receptors rather than TLR‐mediated DC activation is important for viral control.

Adptive immune response to Virus
The immune response to viral infection comprises innate and adaptive defenses. The innate response, which we have discussed previously, functions continuously in a normal host without exposure to any virus. Most viral infections are controlled by the innate immune system. However, if viral replication outpaces innate defenses, the adaptive response must be mobilized.
The adaptive defense consists of antibodies and lymphocytes, often called the humoral response and the cell mediated response. The term ‘adaptive’ refers to the differentiation of self from non-self, and the tailoring of the response to the particular foreign invader. The ability to shape the response in a virus-specific manner depends upon communication between the innate and adaptive systems. This communication is carried out by cytokines that bind to cells, and by cell-cell interactions between dendritic cells and lymphocytes in lymph nodes. This interaction is so crucial that the adaptive response cannot occur without an innate immune system.
The cells of the adaptive immune system are lymphocytes – B cells and T cells. B cells, which are derived from the bone marrow, become the cells that produce antibodies. T cells, which mature in the thymus, differentiate into cells that either participate in lymphocyte maturation, or kill virus-infected cells.
Both humoral and cell mediated responses are essential for antiviral defense. The contribution of each varies, depending on the virus and the host. Antibodies generally bind to virus particles in the blood and at mucosal surfaces, thereby blocking the spread of infection. In contrast, T cells recognize and kill infected cells.
A key feature of the adaptive immune system is memory. Repeat infections by the same virus are met immediately with a strong and specific response that usually effectively stops the infection with less reliance on the innate system. When we say we are immune to infection with a virus, we are talking about immune memory. Vaccines protect us against infection because of immune memory. The first adaptive response against a virus – called the primary response – often takes days to mature. In contrast, a memory response develops within hours of infection. Memory is maintained by a subset of B and T lymphocytes called memory cells which survive for years in the body. Memory cells remain ready to respond rapidly and efficiently to a subsequent encounter with a pathogen. This so-called secondary response is often stronger than the primary response to infection. Consequently, childhood infections protect adults, and immunity conferred by vaccination can last for years.
The nature of the adaptive immune response can clearly determine whether a virus infection is cleared or causes damage to the host. However, an uncontrolled or inappropriate adaptive response can also be damaging. A complete understanding of how viruses cause cause disease requires an appreciation of the adaptive immune response, a subject we’ll take on over the coming weeks.

Conclusions

The effective interplay between the innate and the adaptive immune response represents a key to survival and is essentially controlled through the release of cytokines and chemokines from different cell types initially activated following recognition of viral‐PAMPs. For a depiction of key events in the cellular interplay underlying the antiviral host response to a primary viral infection. The first local response to follow virus attachment and penetration of the epithelial barriers comprises part of the innate immune response, whose purpose is to activate local cell types (e.g. resident macrophages) as well as to recruit and activate DCs and additional antiviral effector cells of the innate defence system to sites of virus replication. As a consequence, local inflammation is induced through the production of inflammatory cytokines and chemokines. In this manner, the viral load is kept low until a more sophisticated adaptive immune response is mounted and effector T cells can be recruited. The second phase of the local host response starts when the first antigen‐specific effector T cells enter the infection site, recognize viral antigen and start releasing their effector cytokines and chemokines including IFN‐γ and TNF‐α. The latter may act in a paracrine fashion to induce neighbouring cells including both resident and recently recruited cells to produce additional cytokines and chemokines. The recruited T‐cells may also directly and/or indirectly augment the expression of important vascular adhesion molecules essential to the extravasation of relevant leucocyte subsets. Together, these events lead to amplification of the local inflammatory response, and recruitment of more effector cells.