T Cell Ontogeny and Major Histocompatibility Complex Specificity

Allografts induce alloimmune responses because of the recognition of nonself antigens (e.g., MHC) from the graft by recipient T cells. During T cell ontogeny during embryogenesis, multilineage bone marrow precursors migrate to the thymus, where ultimate rearrangement of the T cell receptor (TCR) gene occurs, resulting in irrevocable T cell commitment. TCR gene rearrangement is random and ensures that a diverse repertoire of T cells exists to be able to respond to the enormous number of potential foreign antigens.¹¹ The mature T cell repertoire is determined in the thymus by two processes, positive and negative selection. Positive selection is dependent on a certain degree of antigen-specific T cell affinity to self-MHC molecules expressed on thymic cortical epithelial cells. This process ensures that mature T cells will interact effectively with MHC to allow recognition of foreign antigen in the context of self-MHC. Negative selection then occurs by deletion of T cells with excessively high affinity for self-peptide and MHC, thereby preventing release of high-affinity T cells with autoimmune potential.

Mature T cells expressing their clone-specific TCRs then exit the thymus as either CD4 or CD8 T cells. The TCRs of CD4 T cells (also called helper T cells) are selected to interact with class II MHC molecules, whereas the TCRs of CD8 T cells (precursors of cytotoxic T lymphocytes or CTLs) interact with class I MHC molecules. A fundamental principle of immunology is that T cells do not recognize intact foreign proteins directly, but instead as peptides presented by self-MHC on APCs. However, allelic variation among MHC molecules from individual to individual is quite small, resulting in similarities between donor and recipient MHC structure. Thus, unique to the transplant setting, recipient TCRs have a strong affinity for intact donor MHC molecules and can recognize them directly, which explains in large part the high proportion of T cells responding to alloantigen.¹² In fact, only 1/10⁵ to 1/10⁶ T cells will respond to any given nominal antigen (e.g., peptide derived from tetanus toxin or influenza hemagglutinin). However, the frequency of T cells that respond to foreign MHC molecules (alloantigens) is much higher (up to 5% to 10% of all T cells).

Pathways of Allorecognition

Recipient T cells may encounter alloantigen by either the direct or indirect pathways of allorecognition (Fig. 100-2). As previously alluded to, direct antigen presentation involves recipient T cell recognition of donor MHC peptides in the peptide groove of intact donor MHC molecules on the surface of donor APCs. By this mechanism, donor APCs migrate from the graft to recipient lymphoid organs and activate alloreactive recipient T cells to initiate the alloimmune response. It has been suggested that the direct pathway may be particularly active early after transplantation, when a large number of donor APCs are present in the allograft. However, direct antigen presentation may also occur later when recipient T cells recognize intact donor MHC molecules on cells of the graft (e.g., endothelium). The best evidence of direct allorecognition is the strong in vitro response generated in the mixed lymphocyte reaction (MLR), whereby lymphocytes are cultured with allogeneic APCs. B cells also recognize intact donor MHC antigen via their B cell receptors (BCRs).

Indirect antigen recognition is the physiologic mechanism of foreign antigen presentation. Foreign antigen is taken up by APCs, processed intracellularly, and then presented as peptides on MHC molecules. During indirect allorecognition, donor MHC molecules are shed from the graft and processed by recipient APCs, where they are presented as peptides to recipient T cells in the context of recipient MHC molecules.¹³ Because donor MHC molecules are continually shed from the graft and presented by recipient APCs, indirect allorecognition may play a larger role in the late alloresponse, including chronic rejection. However, the relative contribution of direct versus indirect allorecognition to the alloresponse at different time points after transplantation remains the subject of debate.

Major Histocompatibility Complex

Class I and II MHC molecules are designed for presentation of antigen from different sources for different purposes (Fig. 100-3). The class I system is designed to sample cytosolic proteins to detect tumors or intracellular pathogens, such as virus and intracellular bacteria. Class I molecules are recognized by CD8 T cells and thus provide a surveillance mechanism to target infected or malignant cells for destruction by CTLs. The class II system is designed to sample extracellular proteins that have been taken up and processed by APCs. Class II molecules are recognized by CD4 T helper cells and allow for the generation of immune responses to invading pathogens that are phagocytosed by APCs. Cross-presentation is a process by which certain APCs take up, process, and present extracellular antigen on class I molecules to CD8 T cells.¹⁴ This mechanism is necessary for immunity against tumors and viruses that do not infect APCs. MHC products also play other important roles, including the positive and negative selection of developing T cells described earlier, stimulation of naive and memory T cells that is necessary for their survival (homeostatic proliferation), the induction of T cell tolerance and anergy, and interaction with NK cells and other inhibitory and activating receptors.

The MHC gene locus (in humans, human leukocyte antigen [HLA]) maps to a 3.5-million–base-pair region on the short arm of chromosome 6 and is divided into three regions: the class II region, the class III region, and the class I region. Only the class I and II regions encode proteins involved in antigen presentation. The key MHC genes are the class I genes (HLA-A, HLA-B, and HLA-C) and the class II genes (HLA-DP, HLA-DQ, and HLA-DR). The class I and II proteins share overall structural homology but are functionally different.¹⁵ The molecular structure of MHC class I and II proteins is presented in Figure 100-3.

Class I proteins are expressed on virtually all nucleated cells, although the amount expressed varies. Class II proteins have a more restricted cell distribution, generally limited to bone marrow–derived professional APCs, including DCs, B cells, macrophages, and Langerhans cells, but also other cells, including renal parenchymal and endothelial cells. Both class I and II antigens can be induced on a variety of cells by interferon-γ (IFN-γ) in synergy with other cytokines during rejection episodes.

Human Leukocyte Antigen Typing and Transplantation

Major histocompatibility complex class I and II genes are highly polymorphic in the regions that encode the peptide-binding groove. These polymorphisms help to ensure survival of the species by increasing the variety of peptides that can be presented to T cells. Thus, MHC polymorphisms decrease the chance of encountering pathogens that induce poor immune responses within a population and therefore could lead to the demise of the species.¹⁶ However, it is also these polymorphisms that predispose to allograft rejection, because the antigen presenting structures of one individual are regarded as foreign by another nonidentical individual.

Originally, polymorphisms were defined by HLA serologic (antibody) typing using sera from multiparous women or persons who had received blood transfusions. The development of molecular biology techniques (polymerase chain reaction [PCR] sequencing) has allowed the analysis of the HLA allelic sequence diversity at the DNA level. By DNA typing, many more polymorphisms (alleles) have been identified: currently 2188 for HLA-A, 2862 for HLA-B, 1746 for HLA-C, and 1393 for HLA-DR, with an increasing number of sequences added each year. The most currently updated source for HLA alleles can be identified at the website www.ebi.ac.uk/imgt/hla. Although PCR techniques allow for rapid DNA sequence-based typing of human populations, serologic methods are still often used for identifying HLA antigens in kidney transplantation.

Human Leukocyte Antigen Inheritance

Human leukocyte antigen genes are inherited in a Mendelian co-dominant fashion, meaning that a copy of each HLA gene (i.e., one haplotype) is inherited from each parent and expressed as antigens. HLA typing identifies the specific alleles carried by a person. The term HLA matching means assigning a donor kidney to a recipient with as few mismatches as possible. In kidney transplantation, efforts are made to match HLA-A, HLA-B, and HLA-DR genes and proteins. It can be predicted that siblings from the same set of parents will have a 25% chance of having zero mismatches, a 50% chance of one haplotype mismatch, and a 25% chance of two haplotype mismatches (Fig. 100-4).

Major histocompatibility complex I-related chain A (MICA) antigens are surface glycoproteins with functions related to innate immunity. Exposure to allogeneic MICA during transplantation can elicit antibody formation.¹⁷ ABO blood group glycolipids expressed on endothelial and red blood cells are other notable non-MHC antigens. Finally, immune responses to autoantigens have been associated with allograft damage.¹⁸

T Cell Receptor

Each T cell bears about 30,000 identical antigen-receptor molecules. Each receptor consists of two different polypeptide chains, termed the TCR α and β chains, which are linked by a disulfide bond. The genes encoding the TCR chains are members of the immunoglobulin (Ig) supergene family, which are found on B, T, and NK cells. The α:β heterodimers are very similar in structure to the Fab fragment of an Ig molecule and account for antigen recognition by most T cells (Fig. 100-5). In contrast to the Ig receptors of B cells, TCRs do not recognize antigen in its native state, but instead recognize a com­posite ligand of a peptide bound to an MHC molecule. A minority of T cells bears an alternative, but structurally similar, receptor composed of a different polypeptide heterodimer (γ:δ).

CD4 and CD8 Coreceptors

T cells fall into two major classes with different effector functions, distinguished by the expression of the cell-surface proteins CD4 and CD8 (see Fig. 100-5). Both CD4 and CD8 have a cytoplasmic tail that can associate with signaling proteins important in T cell activation. CD4 and CD8 binding to MHC are required to make an effective response. Thus, these molecules are called coreceptors.

T Cell Receptor Engagement of Antigen: Signal 1

The TCR α:β heterodimer recognizes and binds its peptide-MHC ligand¹⁹ but cannot signal to the cell that antigen has bound. In the functional receptor complex, α:β heterodimers are associated with a complex of four other signaling chains (two ε, one δ, one γ) collectively called CD3 (see Fig. 100-5). Engagement of the TCR by MHC, along with the other required receptor engagements, initiates the signaling process from the CD3 complex, leading to cell proliferation and differentiation.²⁰

T Cell Costimulation: Signal 2

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