Chapter 11 Regulation of the Immune Response

Summary

• Many factors govern the outcome of any immune response. These include the antigen itself, its dose and route of administration, and the genetic background of the individual responding to antigenic challenge. A variety of control mechanisms serve to restore the immune system to a resting state when the response to a given antigen is no longer required.

• The APC has an important effect on the immune response through its ability to provide co-stimulation to T cells and by the production of cytokines and chemokines that influence both the nature and make-up of the ensuing reponse. In addition, APC heterogeneity aids in the promotion of different modes of immune response.

• T cells regulate the immune response. Cytokine production by T cells influences the type of immune response elicited by antigen. CD4⁺ T cells can differentiate into several effector phenotypes such as TH1, TH2 or TH17. These subsets play important roles in the protection of the host against a diversity of pathogen challenges. Regulatory T cells may belong to the CD4 or CD8 subpopulations. They may inhibit responses via a variety of mechanisms such as via cell-to-cell contact or by the production of the anti-inflammatory cytokines IL-10 and TGFβ.

• Immunoglobulins can influence the immune response. They may act positively, through the formation of immune complexes, or negatively, by reducing antigenic challenge or by feedback inhibition of B cells.

• Selective migration of lymphocyte subsets to different sites can modulate the local type of immune response because different TH subsets respond to different sets of chemokines.

• The neuroendocrine system influences immune responses. Cells from both systems share similar ligands and receptors, which permit cross-interactions between them. Corticosteroids in particular downregulate TH1 responses and macrophage activation.

• Genetic factors influence the immune system and include both MHC-linked and non-MHC-linked genes. They affect the level of immune response and susceptibility to infection.

Ideally, an immune response is mounted quickly to clear away a pathogenic challenge with the minimum of collateral damage and then the system is returned to a resting state once the antigen is eliminated. The immune response, like many other biological systems, is therefore subject to a variety of control mechanisms. Additional mechanisms help regulate the levels of immunopathology that are often a necessary sacrifice for pathogen elimination. An insufficient immune response can result in an individual being overwhelmed by infection. An inappropriate, or over vigorous immune response can lead to high levels of immunopathology or even autoimmunity (see Chapter 20). The balance between these two is therefore critical.

At its most basic, an effective immune response is an outcome of the interplay between antigen and a network of immunologically competent cells. The nature of the immune response, both qualitatively and quantitatively, is determined by many factors, including:

• the form, dose, and route of administration of the antigen;

• the antigen-presenting cell (APC);

• the genetic background of the individual;

• any history of previous exposure to the cognate antigen; and

• any concurrent infections that the individual may have.

Specific antibodies may also modulate the immune response to an antigen.

Regulation by antigen

T cells and B cells are activated by antigen after effective engagement of their antigen-specific receptors together with appropriate co-stimulation. Repeated antigen exposure is required to maintain T and B cell proliferation, and during an effective immune response there is often a dramatic expansion of specifically reactive effector cells.

At the end of an immune response, reduced antigen exposure results in a reduced expression of IL-2 and its receptor, leading to apoptosis of the antigen-specific T cells. The majority of antigen-specific cells therefore die at the end of an immune response leaving a minor population of long-lived T and B cells to survive and give rise to the memory population.

Q. What process leads to the inactivation of T cells and loss of the IL-2 receptor?

A. Ligation of CTLA-4, the alternative receptor for the co-stimulatory molecule B7 (see Fig. 8.17).

Different antigens elicit different kinds of immune response

Intracellular organisms such as some bacteria, parasites, or viruses induce a cell-mediated immune response. Cell-mediated immune responses are also induced by agents such as silica. In contrast, extracellular organisms and soluble antigens induce a humoral response, with the polysaccharide capsule antigens of bacteria generally inducing IgM responses.

In some situations, antigens (e.g. those of intracellular microorganisms) may not be cleared effectively leading to a sustained immune response. Chronic immune responses have several possible pathological consequences and can lead to autoimmunity and hypersensitivity (see Chapters 20 and 23–26).

Large doses of antigen can induce tolerance

Very large doses of antigen often result in specific T – and sometimes B – cell tolerance.

Administration of antigen to neonatal mice often results in tolerance to the antigen. It was once speculated that this might be the result of immaturity of the immune system. However, neonatal mice can develop efficient immune responses (Fig. 11.1) and their non-responsiveness may in some cases be attributable, not to the immaturity of T cells, but to immune deviation. In this case a non-protective TH2-type cytokine response would dominate a protective TH1-type cytokine response.

Fig. 11.1 Effect of antigen dose on the outcome of the immune response to murine leukemia virus

Newborn mice were infected with either 0.3 or 1000 plaque-forming units (pfu) of virus and the CTL response against virally infected targets was assessed together with the production of interferon-γ (IFNγ – a TH cell type 1 [TH1] cytokine) or interleukin-4 (IL-4 – a TH2 cytokine) in response to viral challenge. Mice infected with a low dose of virus make a TH1-type response and are protected. The results are presented as arbitrary units.

T-independent polysaccharide antigens have been shown to generate tolerance in B cells after administration in high doses. Tolerance and its underlying mechanisms are discussed in Chapter 19.

Antigen route of administration can determine whether an immune response occurs

The route of administration of antigen has been shown to influence the immune response:

• antigens administered subcutaneously or intradermally evoke an active immune response; whereas

• antigens given intravenously, orally, or as an aerosol may cause tolerance or an immune deviation from one type of CD4⁺ T cell response to another.

For example, rodents that have been fed ovalbumin do not respond effectively to a subsequent challenge with the corresponding antigen. This phenomenon may have some therapeutic value in allergy. Studies have shown that oral administration of a T cell epitope of the Der p1 allergen of house dust mite (Dermatophagoides pteronyssimus) could tolerize to the whole antigen. The potential mechanisms of such tolerance induction include anergy, immune deviation, and the generation of regulatory T cells that act through the production of cytokines such as TGFβ and IL-10.

Similar observations have been made when antigen is given as an aerosol. Studies in mice have shown that aerosol administration of an encephalitogenic peptide of myelin basic protein (MBP) inhibits the development of experimental allergic encephalomyelitis (EAE) that would normally be induced by a conventional (subcutaneous) administration of the peptide (Fig. 11.2).

Fig. 11.2 Aerosol administration of antigen modifies the immune response

Mice were treated with a single aerosol dose of either 100 μg peptide (residues 1–11 of MBP) or just the carrier. Seven days later the same peptide, this time in adjuvant, was administered subcutaneously. The subsequent development of experimental allergic encephalomyelitis (EAE) was significantly modified in pretreated animals.

A clear example of how different routes of administration affect the outcome of the immune response is provided by studies of infection with lymphocytic choriomeningitis virus (LCMV). Mice primed subcutaneously with peptide in incomplete Freund’s adjuvant develop immunity to LCMV. However, if the same peptide is repeatedly injected intraperitoneally the animal becomes tolerized and cannot clear the virus (Fig. 11.3).

Fig. 11.3 Peptide-induced inactivation of LCMV-specific T cells

Mice were either primed with LCMV or injected with 100 mg LCMV peptide. The peptide was given either subcutaneously (s.c.) or three times intraperitoneally (i.p.) with incomplete Freund’s adjuvant. The animals were later infected with LCMV (day 0). The titer of virus in the spleen was measured on day 4. Animals that had been pretreated with subcutaneous peptide or with LCMV developed neutralizing antibody and protective immunity against the virus; animals pretreated with peptide i.p. did not develop immunity. Cytotoxic T lymphocyte (CTL) activity was assessed in the mice on day 10. Mice that had received no pretreatment demonstrated CTLs specific for the LCMV peptide. Mice pretreated with peptide i.p. failed to show such activity.

Regulation by the antigen presenting cell

The nature of the APC initially presenting the antigen may determine whether immune responsiveness or tolerance ensues. Effective activation of T cells requires the expression of co-stimulatory molecules on the surface of the APC. Therefore, presentation by dendritic cells or activated macrophages that express high levels of MHC class II molecules, in addition to co-stimulatory molecules, results in highly effective T cell activation. Furthermore, the interaction of CD40L on activated T cells with CD40 on dendritic cells is important for the high-level production of IL-12 necessary for the generation of an effective TH1 response.

If antigen is presented to T cells by a ‘non-professional’ APC that is unable to provide co-stimulation, unresponsiveness, or immune deviation results. For example, when naive T cells are exposed to antigen by resting B cells they fail to respond and become tolerized. Experimental observations illustrate this point.

Neonatal animals are more susceptible to tolerance induction. Therefore mice administered MBP in incomplete Freund’s adjuvant during the neonatal period are resistant to the induction of EAE. This is due to the development of a dominant TH2 response (see Fig. 11.1). The prior TH2 response to MBP prevents the development of the TH1/TH17 pathological response, which mediates EAE. This effect is not restricted to neonatal animals. Indeed, adult Lewis rats can be tolerized to the induction of EAE by similar administration of MBP in incomplete Freund’s adjuvant.

Adjuvants may facilitate immune responses by inducing the expression of high levels of MHC and co-stimulatory molecules on APCs. Furthermore, their ability to activate Langerhans’ cells leads to the migration of these skin dendritic cells to the local draining lymph nodes where effective T cell activation can occur.

The importance of dendritic cells in initiating a cytotoxic T lymphocyte (CTL) response is illustrated by experiments showing that newborn female mice injected with male spleen cells fail to develop a CTL response to the male antigen, H-Y. However, if male dendritic cells are injected into female newborn mice, a good H-Y-specific CTL response develops.

Cytokine production by APCs influences T cell responses

Cytokines are part of an extracellular signaling network that controls every function of the innate and adaptive immune system and have:

• numerous effects on cell phenotypes; and

• the ability to regulate the type of immune response generated and its extent.

Activation of APCs by pathogen stimulation can lead to the production of cytokines and the expression of costimulatory molecules. The local cytokine milieu is heavily influenced by cytokines derived from innate immune cells in the early stages of an immune response. For instance the production of type one interferons and IL-12 in response to viral challenge will evoke cell-mediated immunity by the polarization of naive CD4⁺ T cells to the TH1 phenotype. Conversely early production of IL-4 by innate immune cells will cultivate a humoral TH2 response and act to inhibit any TH1 response.

Q. Aside from driving effector T cell responses, how else may APCs affect T cell responses?

A. Dendritic cells or macrophages may produce cytokines such as TGFβ and IL-10 in response to some antigens. These cytokines can drive the conversion of naive CD4⁺ T cells into regulatory T cells (see Fig. 11.8), which can act as suppressors.

T cell regulation of the immune response

Differentiation into CD4⁺ TH subsets is an important step in selecting effector functions

A single TH cell precursor is able to differentiate into a variety of phenotypes, the best characterized and understood being the TH1 and TH2 phenotypes. A recently-described subset, TH17 (producing IL-17A and IL-17F), is proposed to have important roles in mucosal immunity to certain bacteria and fungi. The differentiation fates of TH cells are crucial to the generation of effective immunity; factors that may influence the differentiation of TH cells include:

• the sites of antigen presentation;

• co-stimulatory molecules involved in cognate cellular interactions;

• peptide density and binding affinity – high MHC class II peptide density favors TH1 or TH17, low densities favor TH2;

• APCs and the cytokines they produce;

• the cytokine profile and balance of cytokines evoked by antigen;

• receptors expressed on the T cell;

• activity of co-stimulatory molecules and hormones present in the local environment;

• host genetic background.

The cytokine balance controls T cell differentiation

IL-12 is a potent initial stimulus for IFNγ production by T cells and natural killer (NK) cells and therefore promotes TH1 differentiation. IFNα, a cytokine produced early during viral infection, induces IL-12 and can also switch cells from a TH2 to a TH1 profile.

By contrast, early production of IL-4 favors the generation of TH2 cells. NKT cells, specialized macrophages (called alternatively activated macrophages) and basophils have all been suggested to be early producers of IL-4.

Very recent studies have suggested the existence of a novel TH2 promoting innate cell population present in gut associated lymphoid tissues (GALT). These cells respond rapidly to the cytokines IL-25 and IL-33, which can be produced by epithelial cells, in response to antigens derived from helminths or allergens. These cells have been reported to produce large amounts of IL-5 and IL-13, with lesser amounts of IL-4.

TH17 cells in mice develop in the presence of TGFβ with IL-6 or IL-21 and share an interesting reciprocal developmental relationship with inducible Tregs, which is discussed in more detail below.

Cytokines from the various TH subsets can cross-regulate each other’s development. Thus, cross-regulation of TH subsets has been demonstrated whereby IFNγ secreted by TH1 cells can inhibit the responsiveness of TH2 cells; also IL-17A can inhibit the development of TH1 responses (Fig. 11.4) whereas IL-10 produced by TH2 cells downregulates B7 and IL-12 expression by APCs, which in turn inhibits TH1 activation.

Fig. 11.4 Differentiation of murine TH cells

IL-12 and IFNγ favor differentiation of TH1 cells, and IL-4 favors differentiation of TH2 cells. TGFβ and IL-6 will drive TH17 cell development. (GM-CSF, granulocyte–macrophage colony stimulating factor; TNF, tumor necrosis factor.)

The TH subset balance is modulated not only by the level of expression of cytokines such as IL-12 or IL-4, but also by expression of cytokine receptors. For instance, the high-affinity IL-12R is composed of two chains, β1 and β2, with both chains being constitutively expressed on TH1 cells. TH1, TH2, and TH17 cells express the β1 chain, but expression of the β2 chain is induced by IFNγ and inhibited by IL-4 (Fig. 11.5). Therefore cytokines reinforce the lineage decisions of the various TH subsets at least in part by controlling the expression of lineage specific receptors.

Fig. 11.5 Regulation of the TH1 response by IL-12

The high-affinity IL-12R consisting of the β1 and β2 chains is constitutively expressed on TH1 cells. IL-12 released by mononuclear phagocytes promotes the development and activation of TH1 cells, but IL-12 production is inhibited by IL-10 released by TH2 cells. IFNγ from TH1 cells promotes production of the β2 chain and therefore production of the high-affinity IL-12R. However, this is inhibited by IL-4.

An immune response therefore tends to settle into a TH1, TH2 or TH17 type of response, but immune responses are not always strongly polarized in this way particularly in humans. It is conceptually useful to consider TH1 and TH2 as extremes on a scale, and TH1 and TH2 responses do play different roles both in immune defence and immunopathology. However it is important to appreciate that other TH subsets such as TH17 do exist and that the well-established TH1/TH2 paradigm is an oversimplification. It should also be noted that some recent studies have suggested that many TH subsets are in fact not terminally differentiated; and when given the right signals; some TH cells can undergo conversion to another phenotype.

Q. Apart from the cross-regulation by cytokines described above, in what other ways can a TH1- or TH2-type immune response reinforce itself?

A. The chemokines induced by TH1 and TH2 cells tend to induce the accumulation of the same sets of lymphocytes and their associated effector cells (see Chapter 6).

T cell plasticity

Recently, studies of TH cells have revealed considerable developmental plasticity. In particular, TH17 cells can be induced to produce IFNγ (a TH1 cytokine) and shut down production of IL-17A if they are stimulated in the presence of IL-12 (Fig. 11.w1). Similarly, at least in vitro, TH2 cells can be driven to a mixed TH2/1 phenotype by culture with type one IFNs and IL-12, where cells co-express IL-4 and IFNγ. The reasons for this flexibility in cytokine production remains to be further explored, but it is thought that such plasticity may enable rapid site-specific immune responses to infections to occur.

Fig. 11.w1 TH17 differentiation

TH17 cells can differentiate into TH1 cells, depending on the local cytokine milieu.

Additionally, induced Foxp3⁺ Tregs have also been shown to exhibit phenotype instability. Some proposed therapeutic strategies for the treatment of autoimmune disorders have postulated the idea of using Tregs, either derived or generated from affected patients, to suppress unwanted immune responses. It is, therefore, critical to understand the factors that govern lineage commitment and plasticity of T cells. This is currently a fast-moving field of research, but despite some controversies there is a growing consensus that T cell plasticity may in fact be the norm and not the exception.

TH cell subsets determine the type of immune response

It is clear that:

• local patterns of cytokine and hormone expression help to select lymphocyte effector mechanism; and

• the polarized responses of CD4⁺ TH cells are based on their profile of cytokine secretion (Fig. 11.6).

Fig. 11.6 Selection of effector mechanisms by TH1 and TH2 cells

The cytokine patterns of TH1, TH2 and TH17 cells drive different effector pathways. TH1 cells activate macrophages and are involved in antiviral and inflammatory responses. TH2 cells are involved in humoral responses and allergy. TH17 cells are an important defense at mucosal barriers recruiting neutrophils to sites of infection and tightening epithelial barriers.

Q. In what way do cytokines that are normally associated with TH1 responses (IFNγ, IL-2) affect B cell differentiation?

A. IL-2 promotes B cell division. IFNγ promotes affinity maturation and class switching to IgG2a, which acts as an opsonin and fixes complement.

TH1 cytokines including IFNγ, TNFβ, and IL-2 also promote:

• macrophage activation;

• antibody-dependent cell-mediated cytotoxicity; and

• delayed-type hypersensitivity.

TH2 clones are typified by production of IL-4, IL-5, IL-9, IL-10 and IL-13 (see Fig. 11.4). These cells provide optimal help for humoral immune responses biased towards:

• IgG1 and IgE isotype switching;

• mucosal immunity;

• stimulation of mast cells, eosinophil growth and differentiation; and

• IgA synthesis.

TH17 cell cytokines include IL-17A, IL-17F, TNFα, and IL-22. Since many stromal cells express receptors for these cytokines the effects of TH17 cells can promote inflammation. In addition:

• IL-17A has been proposed to be important for the recruitment of neutrophils and induction of anti-microbial peptides from resident cells.

• IL-17A is important for host defence against Klebsiella pneumonia and Candida albicans.

Therefore, in essence, TH1 cells are associated with cell-mediated inflammatory reactions and TH2 cells are associated with strong antibody and allergic responses. TH17 cells appear important in defense against certain infections, particularly at mucosal surfaces.

CD8⁺

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