Cell mediated immunity against viruses

Binding of these effector cells to the Fc portion of IgG bound to the infected-cell surface antigens results in lysis of the infected cell. ADCC is a very efficient way of lysing virus-infected cells because it requires significantly less antibody than does antibody-complement lysis. Lymphocytes, macrophages, and neutrophils are all capable of mediating ADCC against virus infected cells. The lymphocytes with this ability appear to be heterogeneous.

Macrophages are important in both specific and nonspecific responses to viral infections e. Factors that modify macrophage activity can influence the outcome of an infection. Moreover, since macrophages are central to the induction of T and B lymphocyte responses, any effect on macrophages will influence B and T cells. Macrophages confer protection against viruses through either an intrinsic or an extrinsic process.

In the former, virions are disposed of within macrophages acting either as phagocytes or as nonpermissive host cells. In the latter case, macrophages retard or ablate virus multiplication in neighboring cells by destroying virus-infected cells or by producing soluble factors interferons that act on these cells.

Phagocytosis of some viruses by macrophages decreases virus levels in body fluids as during viremia and thereby impedes virus spread. These effects are produced only if the virus is destroyed or contained by macrophages. If a virus replicates in macrophages, the infected macrophages may aid in transmission of the virus to other body cells. The permissiveness of macrophages for virus replication may depend on the age and genetic constitution of the host and on the specific condition of the macrophages.

Macrophage activation mediated either by products of infection viral and cellular or by soluble factors produced by T cells e. Another important effector mechanism of activated macrophages is their ability to recognize and destroy virus-infected and virus-transformed cells Fig.

In addition, activated macrophages participate in virus inhibition by producing cytokines interferon, etc. Natural killer NK cells exhibit cytotoxic activity against a number of tumor cell lines, particularly against virus-infected or virus-transformed cells Fig. Natural killer or natural killer-like cells, which have been found in almost every mammalian species examined and even in some invertebrates, are identified as large granular lymphocytes that possess Fc receptors.

They can mediate ADCC activity; their nonspecific cytotoxic activity is increased by interferon and interleukin-2 IL-2 ; and they can produce a number of different cytokines including interferon when stimulated with virus or virus-infected cells.

Although natural killer cells display cytotoxic activity against virus-infected or transformed cells, they show little or no cytotoxic activity against normal cells. Unlike that of cytotoxic T lymphocytes, natural killer cell killing is not human leukocyte antigen HLA restricted, and natural killer cells do not exhibit conventional immunologic specificity. There is evidence that natural killer cells play an important defensive role in virus infections in humans and animals.

Their importance is believed to be due to their ability to produce cytokines and to kill virus-infected cells. Soluble factors from T lymphocytes lymphokines and macrophages monokines regulate the degree and duration of the immune responses generated by T lymphocytes, B lymphocytes, and macrophages see Ch. Interleukin-2 and gamma interferon are two such important factors produced by activated T cells. Interleukin-l is a soluble factor produced by macrophages.

All three of these factors are essential for the full differentiation and proliferation of cytotoxic T cells. The two interleukins are also important for antibody production by B lymphocytes. Macrophages and T lymphocytes also produce several other important factors that act in both the immune and the inflammatory responses.

Gamma interferon can activate macrophages to become cytotoxic toward virus-infected cells and can increase the level of phagocytosis and degradation. Lymphotoxins produced by T cells also may participate in the destruction of virus-infected cells. Virus can stimulate alpha interferon production from macrophages; this enhances natural killer cell function and inhibits virus multiplication in neighboring cells.

A host clearly has numerous mechanisms to recognize and eliminate the viruses that it encounters. However, some viruses persist despite these mechanisms, and then the immune responses may become detrimental to the host and cause immune-mediated disease.

When an antigen virus persists, pathologic changes and diseases result from different types of immunologic interactions, including immediate hypersensitivity, antibody-mediated immune complex syndrome, and tissue damage caused by cell-mediated effector cells and antibody plus complement. Of these mechanisms, the immune complex syndrome during viral infections has been studied most intensively.

Two major complications of deposition of immune complexes are vascular damage and nephritis. Some viral diseases in which immune complexes have been demonstrated are hepatitis B, infectious mononucleosis, dengue hemorrhagic fever, and subacute sclerosing panencephalitis. Cytotoxic T cells also mediate immunopathologic injury in murine models of human infections i.

Both cytotoxic T cells and T cells responsible for delayed-type hypersensitivity have also been implicated in the pathology associated with influenza pneumonia and coxsackievirus myocarditis of mice. A delicate balance between the removal of infected cells that are the source of viral progeny and injury to vital cells probably exists for T cells as well as for the other host immune components.

Viruses may sometimes circumvent host defenses. An important factor that may impair the function of sensitized T lymphocytes is apparent from the observation that T cells activated by reaction with antigen or mitogen lose their normal resistance to many viruses.

Therefore, these activated T lymphocytes develop the capacity to support the replication of viruses, leading to impairment of T lymphocyte function. On the basis of the mechanisms described here and in Chapter 49 , a hypothetical model can be constructed that shows how the immune components defend against viruses Fig.

A primary infection in a nonimmune, susceptible host is countered first by the nonspecific defense mechanisms see Ch. The early nonspecific responses occur within hours and consist of interferon production, inflammation, fever, phagocytosis, and natural killer cell activity. These defenses may prevent or abort infection; if they do not, the virus is disseminated by local spread, viremia, or nerve spread.

It then may seed to a number of target organs and thereby produce a generalized infection. The events that lead to a specific immune response begin almost immediately after exposure and result in the production of antiviral antibody and cell-mediated immunity in 3 to 10 days. The disseminated antibody response in serum is predominantly IgG preceded by IgM ; the local antibody response in secretions is predominantly secretory IgA with some IgM.

The persistence of IgA antibodies in secretions is much shorter months than the persistence of IgG antibody in serum years. The role of IgE in secretions is unknown, but it may mediate immediate hypersensitivity and amplify the immune response during infection.

Antibodies may neutralize virus directly or destroy virus-infected cells via ADCC or complement. Clearly, serum antibody confers protection against generalized infections e. In localized infections of mucosal surfaces, protection does not correlate with the presence of serum antibody, but it does correlate with the presence of local IgA antibody, as has been shown in human studies of viruses restricted to the respiratory tract e.

Under some conditions in which serum antibody is present but local IgA is absent, hypersensitivity instead of protective immunity may occur e. Also, serum antibody may not protect against recurrence of latent infections, such as herpes zoster shingles and herpes simplex, both because the virus may be shielded by its intracellular location and because cell-mediated immunity may be the more important defense.

Antibody may also cause undesirable effects in certain chronic infections. Examples in which small amounts of serum antibody complex with virus and deposit in the kidneys, thereby inducing immune complex disease, are listed in Table Therefore, serum IgM and IgG antibody seem to be effective in preventing infections of a generalized nature; however, in localized surface infections the presence of secretory IgA antibody appears to correlate much better with protection than the presence of circulating IgG antibody.

In persistent infections, serum antibody may be responsible for certain long-term sequelae. Cell-mediated immunity is essential in recovery from and control of viral infections, especially infections involving oncogenic viruses or viruses that spread directly from cell to contiguous cell.

In these situations antibody cannot reach the virus but virally induced antigens on the surface of the infected cell can be recognized by different effector cells e. If the virus reaches target organs, it is more difficult to control. The host defenses that may play important roles in target organs are initially inflammation, fever, and interferon and subsequently cell-mediated immunity.

In some situations, cell-mediated immunity may develop before antibody production begins. For example, cytotoxic effector T cells have been found in bronchial washings 3 to 4 days after initiation of intranasal infection in mice; at this time, antibody cannot yet be detected.

Cell-mediated immune responses can cause tissue damage; the lung lesions produced in influenza may be examples. The lethal effects of lymphocytic choriomeningitis virus in mice are mediated by cytotoxic effector T cells. The rash in many exanthems such as measles is thought to represent a cell-mediated attack on virus localized within cells of the dermis and its vasculature.

Turn recording back on. National Center for Biotechnology Information , U. Show details Baron S, editor. Search term. Chapter 50 Immune Defenses Gary R. These lymphocytes express a variety of antigen-specific molecules that are essential for the detection of infectious agents in the human body. With the help of T cell lymphocytes, in turn activated by MHC class II receptors that recognize microbial-associated antigens, the activated memory B cells express these antigen-specific molecules on their surface while the effector B cells secrete these molecules in the blood to bind the antigen of interest.

Antibodies neutralize antigens primarily through mechanisms of attachment and accumulation. Antibodies can also participate in processes that lead to the lysis or killing of infected or antigen-presenting cells through the activation of the complement cascade or interaction with effector cells and release of cytokines.

The complement system is a part of innate immunity that enhances the ability of antibodies and lymphocytes to clear the body of pathogens and infected cells.

Lastly, antibodies that coat pathogens or infected cells can attract opsonize and become internalized by macrophages during phagocytosis. Kawai T. TLR signaling. Cell Death Differentiation. Garcia-Sastre A. Type 1 interferons and the virus—host relationship: a lesson in detente. Kopp E. Recognition of microbial infection by Toll-like receptors.

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Immunol Rev. Calame K. Transcription factors that regulate memory in humoral responses. Takada A. Antibody-dependent enhancement of viral infection: molecular mechanisms and in vivo implications. Rev Med Virol. Mestecky J. Immunologic uniqueness of the genital tract: challenge for vaccine development.

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J Virol. Sharpe A. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Day C. Virus-induced immunopathology. Adv Virus Res. Cross-genotype protective immunity against HCV was first described in by Lanford et al. This finding, however, has been challenged by other investigators who showed that chimpanzees developed chronic disease after being re-challenged with other genotypes In another study, an HLA-restricted epitope HCV NS and its naturally occurring variants from different genotypes showed that the frequency of cross-reactivity between variants as well as their T cell priming capacities varied, depending on the genotype pair Fytili et al.

The level of cross-reactivity observed in this study could be predicted through in silico analyses of peptide-MHC complexes and TCR-interacting surfaces based on topology and electrostatic features These cells not only reacted to different genotype variants of that epitope but also to epitopes with little sequence similarity of other, unrelated viruses cytomegalovirus, IAV, EBV Immunization with a recombinant adenovirus vector containing mycobacteria, Ebola and HIV antigens also led to T cell responses against HCV alongside the transgenic antigens Cross-reactivity between an HCV and a human herpes virus peptide has also previously been demonstrated Severe hand, foot and mouth disease is caused among others by enterovirus Zhao et al.

Finally, H. Overall, virus-induced H. In this context, prior antigenic exposures may boost protective responses [e. For example, in the case of flaviviruses, it has recently become evident that distinct T cell populations, virus serotypes, sequence, and number of infections, and HLA background all shape the immunodominance pattern Additionally, patterns of T cell cytokine response among patients with a secondary DENV infection were associated with severe 51 , 52 or mild dengue 53 , Although heterotypic antigens were addressed only in one of these studies 52 , such observations may indicate involvement of cross-reactive T cells in the clinical manifestation of DENV infections.

In addition to natural viral infections, antiviral vaccines may also drive T cell-mediated H. To date, epidemiological evidence supporting the role of live attenuated vaccines in T cell-mediated H. Furthermore, they induced changes in the numbers or proportions of T and B cells, which, depending on persistence of effects, may influence differentiation, proliferation or survival of associated cells.

Non-specific effects of vaccines have often been found to be sex-specific and influenced by revaccination as well as maternal priming. In this regard, knowledge on the potential of specific T cell epitopes for any given HLA background to offer protection or cause pathology is crucial for vaccine design including elimination or inclusion of such peptides.

The ability to predict the magnitude and mechanism of T cell-mediated H. Figure 1B is crucial for specific vaccine design but also for decisions on public health and vaccination policies. Structural similarity between T cell epitopes seems to be important for eliciting cross-reactive responses. Nevertheless, seemingly distinct epitopes may also bind to the same TCR and induce H. This may be explained by the fact that sequence similarity is also dependent on the presence of biochemically similar amino acid substitutions In the context of developing broadly cross-reactive vaccines against viruses with great antigenic heterogeneity, regions of highly conserved proteins among serotypes may elicit cross-reactive T memory cell responses.

This approach along with large scale systematic monitoring of circulating strains, as in the case of influenza in order to minimize mismatch with vaccine-contained strains may increase vaccine effectiveness. Besides their specific effect, it is now known that vaccines may also exert a non-specific influence on the immune system For the diphtheria-tetanus-pertussis and measles vaccines, it was shown that the order of vaccination has an impact on overall morbidity and mortality The concept that the most recently administered vaccine leaves a non-specific immunological imprint until subsequent immunization may guide changes in the recommended order of childhood vaccinations.

Such changes could result in beneficial non-specific effects with minor changes of existing national vaccination schemes. Similarly, age at the time of initial or booster immunization with each existing vaccine may need to be reconsidered based on the accumulating knowledge on immunosenescence and effects of age on virus-induced H.

Accordingly, time of vaccination has been linked to differences in T cell populations and strength and type of heterologous immune response 73 , Sex-specific differences in terms of protective non-specific effects of vaccines such as measles and vaccinia 64 , 75 — 80 have also been described. Modification of vaccine composition e. Indeed, adequate application of knowledge regarding vaccine-mediated H.

Administration of live attenuated vaccines to women as part of preconception health counseling is another measure, which could enhance protection of offspring in the first months of life. The potential of virus- and antiviral vaccine-induced immunomodulation may also be exploited for novel applications such as preventing infections among elderly and immunocompromised populations or non-infectious inflammatory diseases. In this respect, the choice of a particular adjuvant or pharmacological modulator is also important since these may polarize T cell immune responses toward a specific cytokine output depending on the desired outcome, e.

The need for new vaccines with higher efficacy and broader and longer-lasting protection is driven by the moderate protection provided by current seasonal influenza vaccines against the included strains, zoonotic and pandemic influenza threats, and the challenge of complying with annual vaccinations. Several approaches are currently being investigated with varying results and distance from truly universal vaccines.

The use of adjuvants, addition of neuraminidase, and inclusion of specific strains induce broader reactive immune responses albeit within the same virus subtype.

Additionally, immunogenic influenza HA-stem constructs induce B cells which produce cross-protective antibodies, at least within a group of viruses. A particular promising approach for the development of truly universal influenza vaccines seems to be the induction of T cells reactive to internal viral proteins, primarily of T rm in the respiratory mucosa for timely control of viral replication.

Such approaches could also prove useful for developing vaccines against other respiratory viruses such as rhinoviruses. Indeed, there is already evidence for cross-reactive immunogenic epitopes contained in these viruses. Properties of virus-induced H. We have previously shown an influenza virus-mediated protection over development of experimental asthma in a murine model. Given the global prevalence of allergies, peptide immunization strategies early in life could potentially induce protective cellular immune responses against viruses and allergen-induced asthma, and complement existing vaccination schedules.

Importantly, directing non-specific beneficial effects of existing live attenuated viral vaccines against other inflammatory disorders including cardiovascular disease and cancer could be a quantum leap in the fight against non-communicable diseases 65 , 81 —