The antigen receptors of B and T lymphocytes have several features that are important for their functions in adaptive immunity (Fig. 1). 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.

Fig1. Properties of antibodies and T cell antigen receptors (TCRs). Antibodies (also called immuno globulins) 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 lym phocytes 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. *The total number of possible receptors with unique binding sites is very large, but only ~107–109 clones with distinct specificities are present in adults. APCs, Antigen-presenting cells; Ig, immunoglobulin; MHC, major histocompatibility complex.

• Membrane-bound antibodies, which serve as the antigen receptors of B lymphocytes, can recognize many types of chemical structures, while T cell anti gen receptors recognize only peptides bound to major histocompatibility complex (MHC) molecules. B lymphocyte antigen receptors and the antibodies that B cells secrete can recognize the shapes, or conformations, of macromolecules, including proteins, lipids, carbohydrates, and nucleic acids, as well as simpler, smaller chemical moieties. This broad specificity of B cells for structurally different types of molecules in their native form enables the humoral immune system to recognize, respond to, and eliminate diverse microbes and toxins. In striking contrast, T cells see only peptides displayed on antigen-presenting cells (APCs) bound to MHC molecules. This specificity ensures that T cells never interact with free or soluble antigens and that they only interact with microbial or tumor antigens present inside other cells in the body.

• Antigen receptor molecules consist of regions (domains) involved in antigen recognition— therefore varying between clones of lymphocytes— and other regions required for structural integrity and effector functions—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 variation 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 following antigen recognition (see Fig. 1). These signals, which are transmitted to the cytosol and the nucleus, may cause a lymphocyte to divide, to differentiate, to perform effector functions, 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 antigen receptors themselves—while leaving the conserved function of signal transduction to the other invariant proteins. The 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 antigens bind to the extracellular portions of the antigen receptors of lymphocytes, intracellular portions of the associated signaling proteins are phosphorylated on conserved tyrosine residues by enzymes called protein tyrosine kinases. 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.

• Antibodies exist in two forms—as membrane-bound antigen receptors on B cells and 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 provide protection against microbes (i.e., they are the effector molecules of humoral immunity). Antibodies are also called immunoglobulins (Igs), referring to immunity-conferring proteins with the physical characteristics 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 B cell activation, 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 next the anti gen receptors of lymphocytes, first antibodies and then TCRs.