**4.2. Interleukin-2 family**

The IL-2 cytokine family, also known as the common γ-chain family, is composed by ILs 2, 4, 7, 9, 15 and 21. All these ILs bind to the common γc receptor, also called CD132. These cytokines act as growth and proliferation factors for progenitors and mature cells [44, 63].

IL-21 is produced by T cells, NKT cells and Th17. The receptor, IL-21, is present in various parts of the human body and consists in CD132 and IL-21R. This cytokine is involved with B cells

In addition to the aforementioned cytokines, other also deserves attention, such as chemokines. The chemokines represent a large family of structurally homologous cytokines that stimulate leukocytes movement and regulate the migration of them from the blood to tissues, in a process named chemotaxis. They control homeostatic immune cells, such as neutrophils, B cells, and monocytes, trafficking between the bone marrow, blood and peripheral tissues.

There are about 50 human chemokines, classified into 4 families according to the location of N-terminal cysteine residues. The two major families are CC and CXC chemokines, in which the cysteine residues are adjacent on CC family, and are separated by one amino acid on CXC family. In general, members of CC chemokines are chemotactic for monocytes, and a small subset of lymphocytes, while CXC chemokines are more specific for neutrophils. The bestknown chemokine is IL-8, or CXCL8, which belongs to the CXC chemokine family, and is responsible for neutrophil recruitment and for the maintenance of the inflammatory reaction. On the other hand, the monocyte chemoattractant protein-1 (MCP-1) or CCL2, and CCL11 or eotaxin, are examples of CC chemokines, which acts on recruitment of a variety of leukocytes,

The chemokines receptors are expressed on all leukocytes and are divided in two groups: G protein-coupled receptors with seven-transmembrane α-helical segments, and atypical receptors, which appear to attenuate inflammation by scavenging chemokines, independently of G protein. Each receptor subtype is capable of binding to various chemokines of the same family, and a single chemokine can bind to more than one receptor. Despite of this factor, a lot of

Chemokines can be produced constitutively in various tissues, and are responsible for regulating the traffic of leucocytes, especially lymphocytes, through peripheral lymphoid tissues. However, the best-known activity of chemokines is the involvement on inflammatory reactions. Recruitment of macrophages, neutrophils and T cells to the site of inflammation is strongly stimulated by chemokines. In fact, they represent a secondary pro-inflammatory mediator that is induced by primary pro-inflammatory mediators, such as IL-1 or TNF. In general, members of the chemokines family induce recruitment of well-defined leukocyte subsets, differently of the classic leukocyte chemoattractants. They induce the movement of leukocytes, and consequently promote their migration to a specific local, by stimulating actin filaments [33, 72–74]. Beyond the involvement of the chemokines on acute inflammatory reactions, and the regulation of the traffic of leukocytes through peripheral lymphoid, independently of the presence of inflammation, some kind of chemokines can promote angiogenesis and wound healing,

T cells, NK cells and NKT. IL-21 is cur-

Cytokines and Interferons: Types and Functions http://dx.doi.org/10.5772/intechopen.74550 77

functions, and also increases the proliferation of CD8<sup>+</sup>

Therefore, they can be classified as chemotactic cytokines [33, 72].

but especially monocytes, and eosinophils, respectively [33, 73, 74].

chemokines presents a great tissue and receptor specificity [72, 73].

rently being studied as anti-cancer therapy [44, 64].

**5. Other cytokines**

IL-2 is the first member of the common γ-chain family, previously known as T cell growth factor. This cytokine is mainly produced by CD4+ and CD8<sup>+</sup> T cells, but can be also expressed by dendritic cells and NKs. The IL-2R is composed by three subunits (CD25, CD122 and common γc), all necessary to binding to IL-2. IL-2 acts in the development of regulatory T (Treg) cells, as a B cell growth factor, stimulates antibody synthesis and promotes proliferation and differentiation of NK cells and T helpers. IL-2 has been extensively used as an anti-cancer therapy [44, 63–65].

IL-4 is produced by Th<sup>2</sup> cells, basophils, eosinophils and mastocytes. It has two receptors: IL4-R type I, which binds only to IL-4 and is composed by CD124 (IL-4rα) and CD 132; and type II, which binds to IL-4 and to IL-13, and it consists in IL-4Rα and IL-13Rα1. These receptors are spread all over the human body. IL-4 is known to play several different roles, regulating allergic conditions and activating the immune response against extracellular parasites (B cell class switching to IgE). It is the main cytokine to stimulate development of Th2 cells. Dupilimab is an IL-4 receptor antagonist approved in 2017 by FDA for treatment of eczema [44, 66, 67].

IL-7 is a homeostatic cytokine. It can be found essentially in T cells, progenitors of B cells and bone marrow macrophages. As the other members of the family, its receptor (IL-7R) consists in the common γ-chain fraction, along with another unit, the IL-7Rα (CD127). IL-7 is involved in the survival and proliferation of thymocytes and in the development of naïve and memory B and T cells, mature T cells and NKs. Deficiencies related to IL-7 result in immunodeficiency, autoimmune diseases and leukemia [44, 68].

IL-9 is mainly produced by Th2 cells, but it is also expressed in less amounts by eosinophils and by mastocytes of asthmatic patients. Its receptor, IL-9R, is composed by the CD132 and IL-9Rα units. IL-9 is a potent growth factor for T cells and mastocytes, and some of it activities include the inhibition of cytokine production by Th1 cells, IgE production, and mucus secretion by bronchial epithelium. Recently, a new subset of effector T cells was discovered, Th<sup>9</sup> , and it is believed that it is intimately related with IL-9 production. IL-9 is associated to allergic diseases and protection from helminthic infections. This cytokine can be found in elevated amounts in Hodgkin lymphoma, hence, IL-9 antagonists are being studied as a potential treatment for this disease [44, 69, 70].

IL-15 is structurally homologous to IL-2. The receptor, IL-15R, is composed by the CD132 subunit common to the family, and also by IL-15Rα and IL-2Rβ chains. IL-15 is produced by keratinocytes, skeletal muscle cells, monocytes and activated CD4+ T cells, in response to signals that trigger innate immunity. IL-15 has some identical functions to IL-2, such as T cell activation and stimulation of NK cell proliferation, but it also involved with CD8<sup>+</sup> memory cell, NK cell, and NKT-cell homeostasis. Increased levels of IL-15 were reported in autoimmune disorders, such as rheumatoid arthritis, psoriasis and celiac disease [44, 71].

IL-21 is produced by T cells, NKT cells and Th17. The receptor, IL-21, is present in various parts of the human body and consists in CD132 and IL-21R. This cytokine is involved with B cells functions, and also increases the proliferation of CD8<sup>+</sup> T cells, NK cells and NKT. IL-21 is currently being studied as anti-cancer therapy [44, 64].
