PRINCIPLES OF TOXICOLOGY

10.2 BIOLOGY OF THE IMMUNE RESPONSE 191
In the specific immune response, antigen may be taken up by APCs and presented to T or B cells.
In order to present the antigen to T cells, the antigen must be processed, or partially digested by the
APC and then presented on its cell surface bound to an MHC class II molecule. Presentation of antigen
to B cells does not require this processing, and in fact B cells are capable of recognizing antigens
directly, without APC presentation. Antigens, either presented by APCs or encountered independently,
interact with immunoglobulins on the cell surface of B-cell clones. Different B-cell clones vary in the
immunoglobulins expressed on their cell surface, and these immunoglobulins can be quite specific in
terms of the antigens with which they will interact. Thus, a particular antigen may interact with only
one or a few B cell clones, a critical aspect in creating a specific immune response. When the antigen
binds to an immunoglobulin receptor on the B cell surface, the antigen–receptor complex migrates to
one pole of the cell and is internalized within the cell. The B cell becomes activated, and the antigen
is processed leading to display of antigenic peptides on the cell surface in conjunction with an MHC
class II protein.
T-cell activation is postulated to require at least two signals. The first signal is thought to be an
interaction between the CD4 + T-cell receptor of T-helper (T H ) lymphocytes and antigenic peptides and
MHC class II proteins presented by APCs or B cells. The second signal may be under the influence of
other receptor–ligand pairs on the T cell and cognate interactions through adhesion molecules of APCs,
MHC complex, and the various cytokines produced by T-cell subsets and accessory cells, such as
macrophages. When activated, T H cells proliferate, creating more cells for interaction with APC and
B cells.
An effective immune response requires the activation of specific subsets of T H cells (T H 1 and
T H 2 cells) which secrete different cytokines. Cytokines are low-molecular-weight proteins that
mediate communication between cell populations. A list and functional classification of cytokines is
shown in Table 10.1. The T H 1 cells are involved in the activation of macrophages by INF-γ, secrete
tumor necrosis factor (TNF), and mediate delayed-type hypersensitivity responses. The most critical
function of T H 2 cells is to regulate B cells, but they also secrete cytokines (specifically, interleukins,
designated IL) that may regulate mast cells (IL3, IL4, and IL10), eosinophils (IL5) and IgE (IL4)
responses in allergic diseases. Of the several factors known to participate in immunomodulation,
IL4 and IL10 are particularly noted to upregulate the humoral response while suppressing the
cell-mediated response (see below for more discussion of humoral versus cell-mediated immunity).
IL13, which is produced by activation of T cells (Table 10.1) and shares many of the properties of
IL4, also suppresses cell-mediated immune responses and the production of proinflammatory
cytokines (IL1, IL6, IL8, IL10, IL12, and TNF).
When an activated T H cell binds to the antigenic peptide-MHC complex of a B cell, the B cell
is stimulated to replicate and differentiate into an antibody secreting plasma cell. This B cell clonal
expansion leads to increased production of antibody specific to that B cell, and this antibody, in
turn, has reactivity directed rather specifically to the antigen initiating the response. Through this
mechanism, the immune system is able to produce the necessary quantities of antibodies targeting
specific molecules (antigens) regarded as foreign. The synthesis of the antibody is tightly
regulated, however, and the proliferation of plasma cells and antibody synthesis are controlled by
cytokines and interactions with T cells. T-amplifier cells (T A ) and T-suppressor cells (T S ), as their
names imply, function to enhance or suppress the immune response, respectively. Control of the
immune response is achieved by balancing the stimulatory and inhibitory effects of T cells and
various cytokines.
After an encounter with an antigen, the immune system appears to retain “memory” of that
antigen and is able to mount a more rapid and greater antibody response on subsequent contact,
even if the period between exposures to the antigen span several years. The basis for this memory
is still not well understood. Initial (primary) immune responses to T-dependent antigens require
a proliferative response by naive T and B cells. As these cells mature, they differentiate and
become effector cells. The elimination of effector T cells and the factors controlling the survival
of memory cells is still controversial. Because immune responses to viruses or immunization
encountered in childhood generally result in lifelong immunity, it has been presumed that memory