*2.2.1 T lymphocytes*

T lymphocytes, effectors of the cell-mediated adaptive response, are divided into two major populations: T helper (Th) lymphocytes, bearing the CD4 receptor, which recognizes antigens presented by the MHC type II molecules, expressed on so-called "professional" APCs (dendritic cells, macrophages, and B lymphocytes), and cytotoxic T lymphocytes (Tc), with the CD8 receptor, which recognizes antigens presented by the MHC type I molecule, expressed on all nucleated cells [7]. CD4 and CD8 are co-stimulatory molecules, which bind to the MHC complex together with the TCR, contributing to T lymphocyte activation, which triggers different signaling cascades acting via various molecules and second messengers [16]. Th cells are critical in coordinating the immune response of other T cells and assist B cells in antibody secretion, whereas Tc cells are involved in the direct removal of damaged, pathogeninfected, or tumor cells. Th cells can develop into T helper 1 (Th1) or T helper 2 (Th2) cells, depending on the context in which antigen presentation occurs. Indeed, the cytokine secretion profile by APCs determines the "fate" of Th lymphocyte differentiation (**Figure 1**). The Th1 response is established in microenvironments where APCs produce essentially IL-12. This cytokine induces T lymphocytes to secrete IL-2 and interferon (IFN)-γ, through which cell-mediated responses, such as the antiviral

### **Figure 1.**

*Different differentiation fates of Thelper cells. Based on the context of antigen presentation and cytokine secretion, Thelper cells can differentiate in different subpopulations with pro- or anti-inflammatory features. The maintenance of the correct balance between them plays an important role for immune homeostasis. Ag, antigen; APC, antigen presentig cell; IFN, interferon; MHC, major histocompatibility complex; TCR, T cell receptor; TGF, transforming growth factor; Th, T helper; TNF, tumor necrosis factor.*

response, are triggered. In particular, IFN-γ activates macrophages, inducing respiratory burst. Other important cytokines activated in this cascade, classically defined as pro-inflammatory, are IL-1, tumor necrosis factor (TNF)-α, and IL-8. In contrast, the Th2 response is associated with the production of IL-4, IL-5, and IL-13 cytokines, which mainly attract eosinophils and mast cells. The Th2 response, particularly involved in parasitic infections and allergies, is also associated with the expression of cytokines, such as IL-10, defined as anti-inflammatory, as they inhibit or reduce inflammatory-type responses. The maintenance of the correct balance between Th1 and Th2 subpopulations plays an important role in inflammation resolution [6]. Other relevant Th lymphocyte subtypes are the Th17, producing IL-17 and IL-22 cytokines, that are important in the response to extracellular pathogens such as fungi and bacteria, but also in some intestinal inflammatory responses; and the regulatory T (Treg) lymphocytes, involved in immune homeostasis especially in the intestine, as they contribute to the maintenance of oral tolerance to nonself harmless antigens, derived from food, but also environmental, such as pollen (**Figure 1**). The correct Th17/Treg balance is now recognized as fundamental for the maintenance of health status, in fact, this equilibrium results altered in many diseases with an autoimmune component, such as inflammatory bowel disease (IBD) [17].

### *2.2.2 B lymphocytes*

B lymphocytes, expressing the surface receptor CD19, are responsible for the production of antibodies (or immunoglobulins), mediators of the adaptive humoral response. Upon encountering antigen, B lymphocytes can differentiate into shortlived antibody-producing plasma cells or long-lived memory cells. Plasma cells produce one of the five classes of immunoglobulins: IgG, IgM, IgA, IgD, and IgE,

### *Immune System, Gut Microbiota and Diet: An Interesting and Emerging Trialogue DOI: http://dx.doi.org/10.5772/intechopen.104121*

each with a specific role. IgM, representing about 10% total Ig in serum, are the first Ig produced in response to a foreign antigen. After 5–6 days from infection normally IgM reach their peak concentration and, thanks to the specific profiles of cytokines released, the so-called "isotypic switch" to IgG occurs. IgG are the predominant and most important class of immunoglobulins, in fact, they represent about 70–75% total Ig in serum. IgG reach the peak of secretion about 14 days after infection and persist for long periods. Normally IgG are the most effective in foreign antigen removal, through the above-mentioned opsonization process, as well as through activation of the complement system [6, 8]. IgD are found in serum at low concentrations (representing less than 1% of all plasma Ig) and their biological functions, related to the regulation of peripheral tolerance to self-antigens and in the maintenance of mucosal homeostasis, involving also host-microbiota interactions, have been elucidated only recently [18]. IgA represent 15–20% serum Ig, but their concentration is higher in secretions (saliva, breast milk, tears, sweat, respiratory, and intestinal secretions) and in the mucosa, i.e., those tissues covering the hollow organs and therefore in contact with the external environment (digestive, respiratory, and genital apparatus), where IgA contribute to preventing microorganisms from adhering to and penetrating inside the body through epithelial cells. In intestinal mucosa, IgA are found in dimeric form (secretory IgA, sIgA), particularly important for the protection against bacteria and viruses from the lumen, but also for the maintenance of oral tolerance to harmless food antigens, as detailed below. IgE, present in serum only in trace amounts, play a role in the removal of extracellular parasites (such as helminths) by opsonization, but are also important mediator in allergic responses. Indeed, IgE bind to a receptor expressed on the membrane of basophils and mast cells, stimulating the degranulation and release of histamine and lipid mediators into the intercellular space, triggering the allergic reaction, as described above [8].

## **2.3 Soluble mediators of the immune response**

Soluble mediators, called cytokines, low molecular weight "messenger proteins" secreted by many cell types, both immune and nonimmune, are involved in both innate and adaptive immune responses. Cytokines send intracellular signals by binding to specific membrane receptors present on the same cells that produced them, or on other target cells, that can be in proximity or not, thus acting in an autocrine, paracrine, or endocrine manner. In general, it is possible to distinguish four different types of cytokines, on the basis of their biological effect: 1 - cytokines produced by leukocytes, having effects on the leukocytes themselves: interleukins; 2 - cytokines with chemoattractant properties, i.e., with a positive effect on cell motility: chemokines; 3 - cytokines that induce differentiation and proliferation of stem cells: colony-stimulating factors; 4 - cytokines that interfere with viral replication: interferons. Cytokines can exert a pro- or anti-inflammatory action, but often the outcome depends on the context of the microenvironment where they are secreted, and on the cells involved [7].
