Page 109 - Clinical Immunology_ Principles and Practice ( PDFDrive )

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Overview of T-Cell Recognition: Making

Pathogens Visible to the Immune System

Andrea J. Sant

ANTIGENS of reactivity to self proteins, leaving cells with the potential to
respond to a diverse set of antigens that may be expressed on
Antibodies and T-Cell Receptors Recognize Antigens pathogens or other “foreign”molecules.
By the late nineteenth century, “antibodies” were the hypothesized Antigens can belong to many different chemical classes and
to be molecular entities that mediated specific immune memory can derive from viral or bacterial proteins, lipids, carbohydrates,
and could neutralize toxins and whose presence resulted in the or combinations of these, such as lipoproteins or glycoproteins.
formation of precipitates when mixed with the molecular species Antigens can also be small chemical compounds, termed haptens
that induced their formation. In almost all cases, evidence for (Fig. 6.2), made synthetically in the laboratory, such as nitrophenyl
the presence of such antibodies required the prior exposure of (NP), or be a natural compound introduced into the host, such
responding animals to the very substances (or ones closely related, as urushiol, the toxin found in poison ivy, which becomes modified
as in the case of toxoids) with which the antibodies reacted. This and antigenic when introduced into the host (Fig. 6.3). Haptens
specific relationship of inducing agent and antibody led to the generally require linkage to a larger host protein or foreign protein
concept of an antigen—the molecular entity that could induce to become immunogenic.
the formation of antibodies specific for it and that could be
recovered in the blood of exposed animals. By developing the Innate Receptors Recognize Pathogen-Associated
concept of the specific receptor, with a specificity analogous to Molecular Patterns or Danger Signal Ligands
the lock-and-key model of enzymes, Paul Ehrlich could explain As a result of advances in the domain of innate immunity, it has
the specificity of antibodies in molecular terms of a reciprocal become challenging, but all the more important, to distinguish
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interaction between a receptor and its binding partner (ligand). between antigens and the many ligands for innate immune
Thus an “antigen” is any molecule that, in whole or in part, binds receptors (Chapter 3). Innate receptor ligands are often described
specifically to the antigen-binding domain of an “antigen receptor” as exhibiting patterns or motifs characteristic of a microbial
(antibody or T-cell receptor [TCR]) (Fig. 6.1). class or physiological condition and the host proteins that rec-
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Ehrlich proposed several tantalizing, but unsatisfying, explana- ognize them as “pattern recognition receptors.” Many of these
tions for the other critical property of antigens—that they induce innate ligands facilitate the host immune system’s recognition
the formation of their own antibodies. This view of antigen is of a pathogen. Included in these innate ligands are Toll-like
that of the vaccinologist, who wants to induce effective immunity receptors (TLRs), which recognize such ligands as bacterial
to an organism expressing that antigen, or of a clinician, who lipopolysaccharide (endotoxin), or viral single- or double-stranded
is wondering why a patient does or does not respond to a RNA. Included among the innate activators are cytosolic DNA
particular allergen, self antigen, or tumor antigen. More than a sensors and nucleotide-binding oligomerization domain (NOD)–
century later, the explanation for the antigenicity of antigens like receptors (NLRs), which recognize bacterial wall peptido-
remains an important and poorly understood issue—why humans glycans and intracellular metabolites induced by cellular damage.
fail to respond adequately to some pathogen or tumor antigens The conceptual difference between antigens and innate receptor
and how vaccines can be improved; why humans respond to ligands lies in the diversity of ligands and the receptors that can
their own self antigens (autoantigens) or antigens present in engage them. The innate immune response recognizes predictable
tissue grafts (alloantigens); and how autoimmune and tissue ligands through binding of a limited set of receptors that recognize
graft-related diseases (graft-versus-host disease [GvHD] and graft these pathogen-derived molecules. The result of this recognition
rejection) can be prevented or treated. The cellular mechanisms is often a rapid production of cytokines or induction of cell-
governing how and when humans respond to antigens remains surface proteins, including host human leukocyte antigen (HLA)
at the cutting edges of both laboratory science and clinical proteins and costimulatory proteins that help activate the adaptive
medicine and are discussed later in this chapter. At the core of immune system. In contrast, the adaptive immune response
this central issue is the defining feature of the immune system— collectively recognizes a wide variety of antigens through a
the distinction between “self” and “nonself.” The host must remain tremendously diverse, but clonally distributed, set of BCRs and
tolerant to its own macromolecules and yet have the capacity TCRs. The function of the specific antigen receptors in the
to respond to its nonself. The molecular components of the adaptive immune responses and the cells that bear them is to
immune system, including cells that display TCRs (T cells) and promote activation and proliferation of the antigen-specific cells,
B-cell receptors (BCRs; antibodies expressed by B cells), undergo leaving the host with memory B cells or T cells that are in higher
developmental events that promote self-tolerance—elimination abundance and often in a poised state after the first encounter.

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