Page 269 - Clinical Immunology_ Principles and Practice ( PDFDrive )

250 PART TwO Host Defense Mechanisms and Inflammation

CD8 T cell
B cell CTL

“help” IFN-γ, Antigen presentation,
IL-2 CCL3/CCL4 IL-12 CCL3/CCL4

“help” IL-12, IL-18, IL-15, IFN-αβ
CD40L expansion/cytotoxicity
NK DC
Lysis/maturation
IFN-γ,TNF
IFN-γ

T helper cell IL-12
CD4 T cell

FIG 17.2 Cellular Interactions During an Immune Response in the Lymph Node. After their
encounter with antigen, dendritic cells (DCs) move to the draining lymph node, where they initiate
an antigen-specific immune response. In the very early stages, natural killer (NK) cells are recruited
to the lymph node and modulate various aspects of this response. NK cells provide cytokines
that induce the maturation of DCs, which enables these cells to efficiently present the antigen
to T cells in the context of costimulatory signals. NK cells also have the ability to eliminate
immature DCs and to provide “early” interferon (IFN)-γ for the initiation of a T-helper 1 (Th1)-type
CD4 T-cell response. Finally, NK cells produce a range of chemokines, most notably chemokine
ligand 3 (CCL3) and CCL4, which are crucial for the recruitment of CD8 T cells into the immune
response.

of CTLs with the selected antigen specificity. The expression of be infected for detection and therefore prevents viruses escaping
CD80/86 is tightly regulated. High-level expression occurs only immune detection by avoiding infection of DCs. Second, viruses
after an APC receives activation signals, such as inflammatory often attempt to evade CTLs by downregulating the MHC class
cytokines, or components of the pathogens such as lipopolysac- I pathway. “Cross-dressing” is a process related to cross-priming
charide. Costimulation via CD28 is most critical during the but involves the direct exchange of preformed peptide–MHC
initiation of the immune response, as it promotes IL-2 production, complexes to uninfected cells. This mechanism acts to significantly
which, in turn, supports the development of effector T cells. amplify the magnitude of priming of T cells, and like cross-
Naïve T cells that receive TCR stimulation in the absence of presentation, potentially circumvents immune evasion strategies
costimulatory signals can become nonresponsive to antigen, a used by pathogens. 7
state termed anergy.
The Contraction of Effector Populations
Cross-Presentation and Priming After activation of CTLs in secondary lymphoid organs, an
After it was established that only direct interaction with an APC immune response is characterized by the rapid proliferation of
and appropriate costimulation led to full CTL activity, a problem antigen-specific cells and their acquisition of effector functions.
arose in explaining the mechanism by which antigens in non-APCs CTLs proliferate at one of the fastest rates known for mammalian
were recognized by CTLs. This dilemma was resolved by the cells, with a cell cycle time of approximately 6 hours. Infection
discovery that there are two distinct mechanisms by which CTLs leads to a dramatic increase in the numbers of pathogen-specific
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encounter peptide–MHC class I complexes. If the APC expresses CTLs, from almost undetectable initial levels to several million
the antigen, for example, if a virus infects it, then the APC can cells in the course of a single week. The magnitude of this response
process the antigen via the endogenous MHC class I pathway is dependent on the kind of infection and the dose of the antigen
for presentation. The more intriguing situation arises when the and is controlled by the number of precursors recruited into
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APC does not express the antigen. In this case, the APC acquires the response. The expansion phase is followed by a contraction
and processes the antigen via a process termed cross-presentation of the CTL population that is independent of both the magnitude
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(Chapter 6). Cross-presentation is initiated by the capture of of the response and clearance of the antigen. This phase is essential
foreign or exogenous antigens by phagosomes. The antigens are to prevent nonspecific tissue damage through uncontrolled
then processed by an unusual mechanism that directs the peptides cytokine release and cytolytic activity. Contraction also preserves
to the MHC class I pathway and presentation on the cell surface. the flexibility of the T-cell response to new infections while
An encounter of a CTL with an antigen processed in this pathway memory of previously encountered antigens is maintained.
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is termed cross-priming. This strategy assists CTLs in viral control Typically, less than 5% of the expanded antigen-specific popula-
in two ways. First, cross-priming alleviates the need for DCs to tion survives in the long-lived memory pool.