Page 24 - Clinical Immunology_ Principles and Practice ( PDFDrive )

10 Part one Principles of Immune Response

APCs and MHC-like molecules in presentation of phosphoan- immunologically naïve cells that have not been previously exposed
tigens to γδ T cells remains a subject of investigation. 31 to antigen. The first signal is provided by antigen. Most commonly,
Another exception to the generalization of T-cell recognition antigens for B cells are proteins with distinct sites, termed epitopes,
of oligopeptides is represented by a group of proteins termed which are bound by membrane Ig. Such epitopes can be linear,
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superantigens (SAgs). SAgs, of which the staphylococcal entero- defined by a contiguous amino acid sequence or (more frequently)
toxin A represents a prototype, are produced by a broad spectrum can be conformationally defined by the three-dimensional
of microbes, ranging from retroviruses to bacteria. They differ structure of the antigen. Epitopes can also be simple chemical
from conventional peptide antigens in their mode of contact moieties (haptens) that have been attached, usually covalently,
both with MHC class II molecules and TCRs (Chapter 6). They to amino acid side chains (Chapter 6). In addition to proteins,
do not undergo processing to oligopeptide fragments but, rather, some B cells have receptors with specificity for carbohydrates,
bind as intact proteins to class II molecules and TCRs outside and less commonly lipids or nucleic acids. Antigens that stimulate
the antigen-binding grooves. Their interaction with TCRs is B cells can be either in solution or fixed to a solid matrix (e.g.,
predominantly determined by variable residues of the TCR Vβ a cell membrane). As previously noted, the nature of antigens
region. Because SAgs bind more or less independently of the that stimulate T cells is more limited. TCRs do not bind antigen
TCRs α chain and the other variable segments of the β chain, in solution but are usually stimulated only by small molecules,
they are capable of activating much larger numbers of T cells primarily oligopeptides, which reside within the antigen-binding
compared with conventional peptide antigens, and hence their cleft of a self-MHC molecule.
name. SAgs cause a wave of T-cell activation, proliferation, and The second signal requisite for lymphocyte activation is
production of proinflammatory molecules that can have profound provided by an accessory molecule expressed on the surface of
clinical consequences, leading to development of such diseases the APC (e.g., B7/CD80) for stimulation of T cells or on the
as toxic shock syndrome. 31 surface of a helper T cell (e.g., CD40L/CD154) for activation of
B lymphocytes. The cell surface receptors for this particular
LYMPHOCYTE ADHESION AND TRAFFICKING second signal on T cells is CD28 and on B cells is CD40 (Fig.
1.3). Other cell surface ligand-receptor pairs may similarly provide
The capacity to survey continuously the antigenic environment the second signal (Chapters 8, 12). The growth and differentiation
is an essential element of immune function. APCs and lympho- of both T cells and B cells additionally requires stimulation with
cytes must be able to find antigen wherever it occurs. Surveillance one or more cytokines, which are peptide hormones secreted in
is accomplished through an elaborate interdigitated circulatory small quantities by activated leukocytes and APCs for function
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system of blood and lymphatic vessels that establish connections in the cellular microenvironment. In the absence of a second
between the solid organs of the peripheral immune system (e.g., signal, cells stimulated only by antigen become unresponsive to
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spleen, lymph nodes, and lymphoid structures in mucosal tissues) subsequent antigen stimulation (anergic) (Chapter 12).
in which the interactions between immune cells predominantly
occur (Chapter 2). T cell B cell
The trafficking and distribution of circulating cells of the
immune system is largely regulated by interactions between mIg + Ag
molecules on leukocyte surfaces and ligands on vascular endo- CD40
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thelial cells (Chapter 11). Leukocyte-specific cellular adhesion
molecules can be expressed constitutively or can be induced by TCR Class II + peptide
cytokines (e.g., as a consequence of an inflammatory process).
Several families of molecules are involved in the regulation of CD28
lymphocyte trafficking. Particularly important are selectins and
integrins, which ensure that mobile cells home to appropriate
locations within lymphoid organs and other tissues. Selectins Up-regulation
are proteins characterized by a distal carbohydrate-binding (lectin)
domain. They bind to a family of mucin-like molecules, the mIg + Ag
endothelial vascular addressins. Integrins are heterodimers CD40L CD40
essential for the emigration of leukocytes from blood vessels TCR Class II + peptide
into tissues. Members of the selectin and integrin families not
only are involved in lymphocyte circulation and homing but are CD28 CD80 (B7)
also important in interactions between APCs, T cells, and B cells
in induction and expression of immune responses. Certain Cytokines
endothelial adhesion molecules, mostly members of the Ig FIG 1.3 Reciprocal Activation Events Involved in Mutual
superfamily, are similarly involved in promoting interactions Simulation of T Cells and B Cells. T cells constitutively express
between T cells and APCs, as well as in leukocyte transmigration T-cell receptors (TCRs) and CD28. B cells constitutively express
from the vasculature. Additionally, receptors for chemokines are mIg and major histocompatibility complex (MHC) class II. Antigen
important determinants of lymphocyte migration, particularly bound to mIg is endocytosed and processed to peptide fragments
in guiding tissue-selective cell trafficking. 33 that bind to MHC class II molecules for presentation to TCRs.
Activation of B cells by antigen (Ag) upregulates their expression
LYMPHOCYTE ACTIVATION of CD80 that interacts with CD28 to activate T cells. This
upregulates CD40L (CD154) on the T cell and induces cytokine
For both B cells and T cells, initial activation is a two-signal synthesis. Costimulation of B cells by antigen, CD40L, and
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event (Chapter 12). This generalization is particularly true for cytokines leads to Ig production.