**2.4. Activation of T cells**

**Figure 2.** A). Allorecognition process. Two pathways lead to T-cell activation, the direct pathway and the indirect pathway. The mechanisms of tolerance are: (B) Central tolerance in which T cells migrate from the bone marrow to the thymus where they are educated, such that those recognizing self-antigens are deleted, and (C) Peripheral mecha‐ nisms of tolerance for self-reactive T cells including AICD, anergy, and suppression by Treg. (D) B-cell awaiting the prop‐ er stimulus of a T-cell to initiate the production of alloantibodies. Two possible scenarios ensure tolerance: deletion of these self-reactive B cells and receptor editing, which is a process by which a new receptor with altered specificity is generated through another sequence of B cell receptor gene rearrangements. Abbreviations: HLA, Human Leukocyte Antigen; APC, Antigen Presenting Cells; TCR, T-cell Receptor; T, T-cell; T reg, regulatory T cells; B, B-cell; IL-2; Interleu‐

A third mode of allorecognition, which Lechler's group has termed the "semi-direct" pathway, has been recently proposed [16]. This model is based on the transfer of intact HLA molecules between cells. DCs have been shown to acquire intact HLA class I and II molecules from exosomes secreted by other DCs and to prime both naïve CD8+ and CD4+ T cells, thereby

Another mechanism of allorecognition involves NK cells. NK cells may recognize HLA classical and non-classical type I molecules through interactions with cell surface receptors called killer cell immunoglobulin-like receptors (KIR, formerly named killer inhibitory

kin-2; AICD, Activation-Induced Cell Death.

**2.3. Other allorecognition pathways**

466 Current Issues and Future Direction in Kidney Transplantation

inducing an alloimmune response [17,18].

Through their specific antigen receptors, T cells are capable of recognizing external antigens and initiating immune responses. These reactions may be characterized predominantly by cellmediated reactions in which effector immune cells play a major role; or by humoral reactions in which the stimulation of B cells (Figure 2D) may induce antibody responses. The T cells orchestrate both the initiation and the propagation of immune responses, largely through the secretion of protein mediators termed cytokines and chemokines. Moreover, recent findings suggest that a novel subtype of T cells, named regulatory T cells, have an important role in achieving allograft tolerance [22]. These facts make T cells important targets for immunosup‐ presive therapy and tolerance induction protocols.

T cells require two separate signals before activation occurs. The first signal is antigen specific and is provided by the interaction of a T cell receptor (TCR) with a peptide antigen presented within the antigen binding groove of HLA molecules on the surface of APCs (Figure 2A). These are HLA class I molecules in the case of CD8+ T cells and class II molecules in the case of CD4+ T cells. The second, costimulatory, signal is provided by the interaction of T cell surface molecules with their ligands on APCs, being the most important the B71 -CD28 and CD40- CD154 interactions. The first signal in the absence of the second signal may lead to T cell inactivation, anergy, or failure of a Th1 (T helper cell-1) response with a switch to a Th2 (T helper cell-2) response [23].

The Th1/Th2 response refers to the pattern of cytokines produced by T helper cells. Th1 cells produce interleukin-12 (IL-12) and interferon gamma (IFN-gamma) inducing macrophage activation leading to delayed-type hypersensitivity responses. The Th1 response has been implicated in acute allograft rejection. Th2 cells produce IL-4, IL-5, IL-10, and IL-13, and provide help for B cell function [24]. IL-4 is a growth factor for B cells and antibody production, and also can directly inhibit T cell maturation along the Th1 pathway [25]. Such responses have been associated with allograft tolerance, but are mainly implicated in clearing parasitic infections and the presentation of allergic diseases.

Once the binding of CD4/CD8 co-receptors stabilizes the immunologic synapse between the T cell and the APC, tyrosine-based activation motifs on the CD3 complex leads to the phos‐ phorylation of a series of intracellular proteins, resulting in the activation of a variety of enzymes including calcineurin, and the activation of transcription factors, such as nuclear factor of activated T cells (NFAT) and NF-κβ, permitting the transcription of different genes,

<sup>1</sup> B7-1 (or CD80) and B7-2 (or CD86).

including HLA class I and IL-2 [26]. There are other important events implicated in the activation of T cells, including leukocyte migration and the interaction of chemokines with their receptors.

anergic. However, if immature B cells are strongly self-reactive, there are two possible scenarios to ensure tolerance. The first is deletion of these self-reactive B cells. The second is receptor editing, a process by which a new receptor with altered specificity is generated

Tolerance in Renal Transplantation http://dx.doi.org/10.5772/54734 469

Besides the deletion process of autoreactive cells occurring during central tolerance, some T or B cells with self-reactivity may escape from the thymus or bone marrow, making the loss of self-tolerance easier. However, several mechanisms, collectively named peripheral toler‐ ance, can control or eliminate such cells. Peripheral tolerance involves deletion and apoptosis,

This mechanism is used to eliminate activated T cells specific for self-antigen. The programmed cell death, or apoptosis, is also termed activation-induced cell death (AICD). This process is mediated by the interaction of Fas (CD95) with its ligand (Fas-L or CD95L) on T cells, and can occur in developing thymocytes as well as mature T cells [33]. IL-2 can activate the STAT 5 sig‐ naling pathway through the IL-2 receptor (IL-2R), which in turn potentiates the up-regulation of Fas-L and the down-regulation of Bcl2 expression on T cells, thus promoting AICD. Con‐ versely, IL-15 acts as a growth and survival factor for T cells [34, 35]. Since augmented AICD can induce tolerance through elimination of populations of reactive lymphocytes [36], certain tol‐ erogenic models which use IL-15 antagonists and IL-2 agonists during transplantation havere‐ sulted in donor-specific tolerance [37]. Further research on this topic is needed before

The hyporesponsiveness of T or B cells to further antigenic stimulation, also called anergy, is a process that can result from antigenic stimulation in the absence of costimulation. In the case of T cells, complete activation requires the presentation of peptide on the HLA molecule to the TCR (first signal), and costimulatory signals, such as the B7-CD28 and CD40-CD154 interac‐ tions (second signal). The second signal is required to induce the multiple pathways that will lead to the activation of IL-2 gene transcription, ultimately inducing T cell activation and proliferation. However, it has been shown that IL-2 production and subsequent signaling through its receptor, IL-2R, is necessary for T cells to escape anergy, since blocking IL-2/IL-2R engagement even after stimulation through the TCR and CD28 still results in induction of T

As with T cell activation, B cell activation requires two signals. In this context, naïve B cells can be anergized if their surface immunoglobulins bind to self-antigens (first signal) in the absence of the additional necessary T cell signals (second or costimulatory signal) [39].

through another sequence of B cell receptor gene rearrangements [32].

anergy, and regulation or suppression (Figure 2C).

considering this peripheral mechanism as a therapeutic approach.

**3.2. Peripheral tolerance**

*3.2.1. Deletion and apoptosis*

*3.2.2. Anergy*

cell anergy [38].
