Antigen Recognition in the Adaptive Immune System - ClinicalKey https://www.clinicalkey.com/#!/content/book/3-s2.0-B9781455... BOOK CHAPTER Antigen Recognition in the Adaptive Immune System Abul K. Abbas MBBS, Andrew H. Lichtman MD, PhD and Shiv Pillai MBBS, PhD Basic Immunology: Functions and Disorders of the Immune System, Chapter 4, 71-91 Antigen receptors serve critical roles in the maturation of lymphocytes from progenitors and in all adaptive immune responses. In adaptive immunity, naive lymphocytes recognize antigens to initiate responses, and effector T cells and antibodies recognize antigens to perform their functions. B and T lymphocytes express different receptors that recognize antigens: membrane-bound antibodies on B cells and T cell receptors (TCRs) on T lymphocytes. The principal function of cellular receptors in the immune system, as in other biologic systems, is to detect external stimuli (antigens, for the antigen receptors of the adaptive immune system) and trigger responses of the cells on which the receptors are expressed. To recognize a large variety of different antigens, the antigen receptors of lymphocytes must be able to bind to and distinguish between many, often closely related, chemical structures. Antigen receptors are clonally distributed, meaning that each lymphocyte clone is specific for a distinct antigen and has a unique receptor, different from the receptors of all other clones. (Recall that a clone consists of a parent cell and its progeny.) The total number of distinct lymphocyte clones is very large, and this entire collection makes up the immune repertoire . Although each clone of B lymphocytes or T lymphocytes recognizes a different antigen, the antigen receptors transmit biochemical signals that are fundamentally the same in all lymphocytes and are unrelated to specificity. These features of lymphocyte recognition and antigen receptors raise the following questions: • How do the antigen receptors of lymphocytes recognize extremely diverse antigens and transmit activating signals to the cells? • What are the differences in the recognition properties of antigen receptors on B cells and T cells? • How is the vast diversity of receptor structures in the lymphocyte repertoire generated? The diversity of antigen recognition implies the existence of many structurally different antigen receptor proteins, more than can reasonably be encoded in the inherited genome (germline). Therefore, special mechanisms must exist for generating this diversity. In this chapter, we describe the structures of the antigen receptors of B and T lymphocytes and how these receptors recognize antigens. We also discuss how the diversity of antigen receptors is generated during the process of lymphocyte development, thus giving rise to the repertoire of mature 1 of 27lymphocytes. The process of antigen-induced lymphocyte activation is described in later chapters.10/29/15, 8:31 PM AntigenAntigen Recognition inReceptors the Adaptive Immune of Lymphocytes System - ClinicalKey https://www.clinicalkey.com/#!/content/book/3-s2.0-B9781455... The antigen receptors of B and T lymphocytes have several features that are important for the functions of these receptors in adaptive immunity ( Fig. 4–1 (f0010) ). Although these receptors have many similarities in terms of structure and mechanisms of signaling, there are fundamental differences related to the types of antigenic structures that B cells and T cells recognize. 2 of 27 10/29/15, 8:31 PM FIGURE 4–1 AntigenProperties Recognition of inantibodies the Adaptive and Immune T cell antigenSystem - receptorsClinicalKey (TCRs). https://www.clinicalkey.com/#!/content/book/3-s2.0-B9781455... Antibodies (also called immunoglobulins) may be expressed as membrane receptors or secreted proteins; TCRs only function as membrane receptors. When immunoglobulin (Ig) or TCR molecules recognize antigens, signals are delivered to the lymphocytes by proteins associated with the antigen receptors. The antigen receptors and attached signaling proteins form the B cell receptor (BCR) and TCR complexes. Note that single antigen receptors are shown recognizing antigens, but signaling typically requires the binding of two or more receptors to adjacent antigen molecules. The important characteristics of these antigen-recognizing molecules are summarized. APCs, Antigen- presenting cells; MHC, major histocompatibility complex. The plasma membrane antibodies that function as antigen receptors of B lymphocytes can recognize a much broader range of chemical structures than the antigen receptors of T cells. B lymphocyte antigen receptors and the antibodies that B cells secrete are able to recognize the shapes, or conformations, of native macromolecules, including proteins, lipids, carbohydrates, and nucleic acids, as well as simple, small chemical groups. This broad specificity of B cells for structurally different types of molecules enables antibodies to recognize diverse microbes and toxins in their native form. In striking contrast, most T cells see only peptides, and only when these peptides are displayed on antigen-presenting cells (APCs) bound to membrane proteins encoded in the major histocompatibility complex (MHC) genetic locus. Thus, T cells are able to detect cell-associated microbes (see Chapter 3 ). Antigen receptor molecules consist of regions (domains) involved in antigen recognition—and therefore varying between clones of lymphocytes—and other regions required for structural integrity and effector functions—and thus relatively conserved among all clones. The antigen-recognizing domains of the receptors are called variable (V) regions, and the conserved portions are the constant (C) regions. Even within each V region, most of the sequence variability is concentrated within short stretches, which are called hypervariable regions, or complementarity-determining regions (CDRs), because they form the parts of the receptor that bind antigens (i.e., they are complementary to the shapes of antigens). By concentrating sequence variation in small regions of the receptor, it is possible to maximize the variability of the antigen- binding part while retaining the basic structure of the receptors. As discussed later, special mechanisms exist in developing lymphocytes to create genes that encode different variable regions of antigen receptor proteins in individual clones. Antigen receptor chains are associated with invariant membrane proteins whose function is to deliver intracellular signals that are triggered by antigen recognition (see Fig. 4–1 (f0010) ). These signals, which are transmitted to the cytosol and the nucleus, may cause a lymphocyte to divide, to differentiate, or in certain circumstances to die. Thus, the two functions of lymphocyte receptors for antigen—specific antigen recognition and signal transduction—are mediated by different polypeptides. This again allows variability to be segregated in one set of molecules—the receptors themselves—while leaving the conserved function of signal transduction in other, invariant proteins. The associated set of plasma membrane antigen receptor and signaling molecules in B lymphocytes is called the B cell receptor (BCR) complex, and in T lymphocytes, it is called the T cell receptor (TCR) complex. When antigen molecules bind to antigen receptors of lymphocytes, 3 of 27 10/29/15, 8:31 PM the associated signaling proteins of the receptor complexes are brought into proximity. As a result, Antigenenzymes Recognition attached in the Adaptive to the Immune cytoplasmic System -portions ClinicalKey of the signalinghttps://www.clinicalkey.com/#!/content/book/3-s2.0-B9781455... proteins catalyze the phosphorylation of other proteins. Phosphorylation triggers complex signaling cascades that culminate in the transcriptional activation of many genes and the production of numerous proteins that mediate the responses of the lymphocytes. We return to the processes of T and B lymphocyte activation in Chapter 5 , Chapter 7 , respectively. Antibodies exist in two forms—as membrane-bound antigen receptors on B cells or as secreted proteins—but TCRs exist only as membrane receptors on T cells. Secreted antibodies are present in the blood and mucosal secretions, where they function to neutralize and eliminate microbes and toxins (i.e., they are the effector molecules of humoral immunity). Antibodies are also called immunoglobulins (Igs), referring to immunity-conferring proteins with the characteristic slow electrophoretic mobility of globulins. Secreted antibodies recognize microbial antigens and toxins by their variable domains, the same as the membrane-bound antigen receptors of B lymphocytes. The constant regions of some secreted antibodies have the ability to bind to other molecules that participate in the elimination of antigens: these molecules include receptors on phagocytes and proteins of the complement system. Thus, antibodies serve different functions at different stages of humoral immune responses: membrane-bound antibodies on B cells recognize antigens to initiate the responses, and secreted antibodies neutralize and eliminate microbes and their toxins in the effector phase of humoral immunity. In cell-mediated immunity, the effector function of microbe elimination is performed by T lymphocytes themselves and by other leukocytes responding to the T cells. The antigen receptors of T cells are involved only in antigen recognition and T cell activation, and these proteins are not secreted and do not mediate effector functions. With this introduction, we describe