IMMUNOLOGY - Roit A. - Mir 2000

Chapter 11. Cell Interactions in the Humoral Immune Response

EFFECTS OF CYTOKINES ON B AND T CELLS

IL-2 plays the primary role in T Cell activation

Lymphocyte proliferation is a complex process mediated by multiple factors. For instance, The stimulation of T Cells by APCs does not mean that the lymphocytes will immediately proliferate. Effective interaction involving the TCR leads to The production of the α-chain (p55) of the T-cell growth factor receptor, IL-2. The α-chain and the pre-existing β (p75) and γ chains associate to form a high-affinity IL-2 receptor (Fig. 11.16). TCR activation in all T cells triggers cytokine production. Most CD4⁺ T cells and some CD8⁺ T cells secrete IL-2 for a short period of 1–2 days. During this time, the interaction of IL-2 with its high-affinity receptor drives T cell growth and activation. Following TCR stimulation, cells express the high-affinity receptor for only about a week: this limitation prevents uncontrolled T cell proliferation, as the lack of positive signals promotes the apoptotic death of redundant cells. A diagram of the entire T cell activation process is shown in Fig. 11.17.

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Fig. 11.16. The high-affinity IL-2 receptor consists of 3 chains, each of which alone binds IL-2 only weakly. Resting T cells do not express the α-chain, but upon activation they can express up to 50,000 α-chains per cell (maximum number). Some of these chains associate with the β-chain to form the high-affinity IL-2 receptor.

Fig. 11.17. Resting cells do not produce cytokines—T-cell growth factors (IL-2, IL-4, or IL-7)—and express only a small number of receptors for IL-4 and IL-7, but not for IL-2. Only the low-affinity p75 chain of the IL-2 receptor is present on their surface. Activation leads to the appearance of the p55 chain, which, together with p75, forms the high-affinity IL-2 receptor.

Activation induces the synthesis of IL-2 and IL-4 mRNA and Proteins. The secretion of these CYTOKINES AND THEIR interaction with receptors drive proliferation. Cytokines act in two ways: autocrine (affecting the cells that produce them) and paracrine (stimulating neighboring cells). In the absence of antigenic stimulation, the number of IL-2 receptors decreases, and the proliferative phase of the Immune Response comes to an end.

IL-2 is synthesized primarily by CD4⁺ T cells, although CD8⁺ cells and large granular lymphocytes (LGLs) are also producers. The action of IL-2 is restricted to specific cell types, mainly all types of T cells, for which this cytokine serves as the most potent growth factor and activator (Fig. 11.18). It also affects LGLs and B cells, inducing their growth and differentiation, and activates macrophages and possibly oligodendrocytes. As a pharmaceutical preparation, IL-2 is used for the experimental therapy of tumors, particularly renal cell carcinoma. The therapeutic effect of this cytokine may be related to the activation of various cells possessing antitumor cytotoxic activity, such as lymphokine-activated killer (LAK) cells.

Fig. 11.18. IL-2 is produced by Th cells. The Functions of this cytokine include the stimulation of T Cell Division, the release of mediators such as IFNγ, the induction of B cell growth, and the activation of monocytes and NK cells to enhance the immune response. Autologous NK cell precursors from patients with renal cell carcinoma can be activated in vitro with high doses of IL-2 (1000 IU/ml) to generate lines of so-called lymphokine-activated killer (LAK) cells, which are used for experimental Cancer therapy.

A less potent T cell growth factor is IL-4, which is also among the inducible cytokines. The expression of the surface receptor for IL-4 is upregulated As a result of TCR activation. T cells are also acted upon by IL-7, although it was originally described as a pre-B-cell growth factor produced by the Bone Marrow stroma. Produced by thymic stromal elements, IL-7 acts on thymocytes, serving as a T cell growth and activation factor In addition to its macrophage-activating property. It is possible that these three growth factors, along with less-studied cytokines such as IL-9, IL-12, and IL-15, exert fine regulation over T cell growth and activation during the immune response.

The cytokines IL-1 and IL-6 serve as costimulatory signaling molecules during T cell activation by certain APCs (Fig. 11.19). Surprisingly, no one has yet managed to detect the production of these cytokines by the APCs considered the most efficient presenting cells in primary T cell activation—interdigitating dendritic cells. It is possible that other cytokines, including IL-12 (produced by dendritic cells) and IL-15, also act as costimulatory molecules.

Fig. 11.19. IL-1 is produced by many cell types in response to injury, infection, or antigen. It affects A wide variety of cells and processes, causing: 1) an increase in the cytotoxic activity of NK cells; 2) an increase in the METABOLIC ACTIVITY OF polymorphonuclear neutrophils (PMNs), which migrate to the site of IL-1 production via chemotaxis (black arrow); 3) the induction of adhesion molecule and procoagulant synthesis in endothelial cells and an increase in endothelial permeability; 4) an increase in prostaglandin and cytokine production by macrophages, as well as their cytocidal and chemotactic (black arrow) activities; 5) the enhancement of Th cell proliferation, IL-2 receptor expression, and cytokine production; and 6) B cell proliferation and their differentiation into antibody-forming cells (AFC) (both processes are regulated by other cytokines (7)).

The cytokine IL-3 stimulates the growth of progenitor cells across all hematopoietic lineages (erythrocytes, granulocytes, macrophages, and possibly lymphocytes). A minor population of T cells (CD4^-CD8^- T cells bearing αβ TCRs) also responds to this cytokine.

B cell activation and division are induced by cytokines produced by Th2 lymphocytes

Specific cytokines produced by Th2 cells include IL-4, IL-5, IL-6, IL-10, and IL-13. The cytokine IL-4 (originally known as B-cell stimulatory factor-1 or B-Cell Differentiation factor) acts on B cells, inducing their activation and differentiation with a preferential production of IgG1 and IgE Antibodies. It also affects T cells as a growth factor, promoting Th2 cell differentiation and thereby enhancing antibody production. Simultaneously, it inhibits the macrophage secretion of pro-inflammatory cytokines such as IL-1 and TNFα. An excess of IL-4, which drives IgE synthesis, plays a pathogenetic role in allergic diseases.

In humans, IL-5 functions primarily as an eosinophil growth and activation factor. In mice, it also acts on B cells, inducing their growth and differentiation. This cytokine is responsible for eosinophilia during parasitic infections.

The cytokine IL-6, formerly known as B-cell differentiation factor or hepatocyte-stimulating factor, is produced by many cells—T lymphocytes, macrophages, B cells, fibroblasts, and endothelial cells. It affects a wide variety of cells, but its most crucial function is inducing the differentiation of B lymphocytes into antibody-forming cells (AFCs). In the Liver, IL-6 stimulates the synthesis of acute-phase proteins. IL-6 is considered an important growth factor for multiple myeloma, a malignancy originating from plasma cells.

Cytokines as regulators of immune responses

The type of developing immune response can also depend on cytokines. The Regulatory Functions of IL-10 and IL-12 are particularly important in this regard. The cytokine IL-10 (also known as cytokine synthesis inhibitory factor) suppresses IFNγ synthesis. Furthermore, it inhibits antigen presentation and the synthesis of IL-1, IL-6, and TNFα by macrophages, which favors The Development of a Th2-type immune response and B cell activation. The action of IL-12 is complementary to the effects of IL-10: it promotes the development of a Th1 response, accompanied by the activation of macrophages and natural killer (NK) cells.

Activated T Lymphocytes and NK cells serve as the source of IFNγ production. Immune activation leads to the production of IFNγ and an increase in the antigen-presenting function of many cell types, including macrophages, astrocytes, microglial and endothelial cells, and thymocytes. This effect is partly mediated by the enhanced expression of class I and class II MHC genes and TAP, which leads to further T cell activation. The expression of the costimulatory molecules B7-1, B7-2, and ICAM-1 is also upregulated. Thus, in many immune reactions, IFNγ functions as a positive feedback regulatory signal. However, at the same time, it inhibits Th2 cell proliferation, generally activates macrophages, and—paradoxically—prevents the induction of class II MHC molecule synthesis on B cells by IL-4. It follows that IFNγ promotes the development of a Th1-type immune response. The properties of IFNγ are illustrated in Fig. 11.20.

Fig. 11.20. Interferon-γ (IFN-γ) exerts numerous immunoregulatory effects. Its antiviral and antiproliferative activities are less pronounced than those of IFN-α and IFN-β. Moreover, it is not as effective at stimulating NK cells as IFN-α. However, IFN-γ serves as the most potent macrophage activator and an inducer of MHC class II molecule expression in tissue cells. Through these and other functions, IFN-γ acts synergistically with TNF-α and TNF-β.

IFN-α and IFN-β, much like IFN-γ, can suppress the proliferation of immune system cells. Furthermore, they inhibit the IFN-γ-Induced Expression of MHC class II Antigens. The cytokine IL-6, while stimulating cell differentiation (including certain leukemic cell lines), inhibits their proliferation. The cytokines IL-6 and IL-11 are capable of inhibiting the macrophage synthesis of pro-inflammatory cytokines, although their effect is weaker than that of IL-4 or IL-10. In its ability to suppress macrophage functions, the cytokine IL-13 is largely similar to IL-4.

Transforming growth factor-beta (TGF-β) is represented by a family of three closely related molecules that stimulate Connective Tissue growth and Collagen formation, while inhibiting virtually all immune and hematopoietic functions, particularly when present prior to cell activation.