Page 440 - Clinical Immunology_ Principles and Practice ( PDFDrive )

420 ParT ThrEE Host Defenses to Infectious Agents

caspase 1 demonstrate increased susceptibility to C. albicans has been demonstrated. Extracellular H. capsulatum are taken
infection. The mechanism appears to be a reduction in neutrophil up by DCs and are then capable of triggering CD8 T cells through
influx. However, in these mouse models, early neutrophil influx antigen-specific peptide-loaded class I MHC molecules.
does not appear to be dependent on an intact inflammasome; Monocyte-derived DCs have a nonredundant role in antifungal
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rather, it is required for sustained neutrophil influx. immunity, through the induction of Th1 cells. CCR2 mice
show skewed Th2 responses and poorly controlled H. capsulatum
MEMORY OF INNATE IMMUNE CELLS infection compared with wild-type control mice. Priming of
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Th1 lymphocytes require CCR2 monocyte-derived inflammatory
Historically, the innate immune response was considered a rapid DCs in mouse models of A. fumigatus or C. neoformans infection.
and nonspecific attack against invading pathogens. The widely These data indicate a critical role for DCs to connect the innate
accepted dogma was that innate immune cells confer no immu- immune response to drive T-cell responses and coordinate the
nological memory, unlike adaptive immune cells that respond adaptive immune response.
more slowly but execute a specific attack based on memory. An
increasing body of evidence suggests that the innate immune THE ADAPTIVE IMMUNE RESPONSE TO
system can, in fact, form memory, challenging the historical FUNGAL PATHOGENS
dogma. For example, innate immune memory has been dem-
onstrated in organisms that lack the adaptive immune system, The primary function of the adaptive immune system is to launch
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such as plants and invertebrates. Several studies have demon- a highly specific attack to destroy invading pathogens. The adaptive
strated increased responsiveness of innate immune cells to second- immune system also provides long-term protection by creating
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ary encounters with pathogens. Immunological memory of “immunological memory” following an initial response to a
innate immune cells has been described in the context of C. pathogen. The two major branches of the adaptive immune
albicans infection; in mice, preexposure to a nonlethal infection system are cell-mediated immunity (CMI) and humoral immunity.
or purified β-1,3 glucan confers protection from a secondary B cells and T cells carry out this adaptive immune response.
lethal infection in the absence of functional B cells and T cells. CMI by T cells is critical for the host response to fungal pathogens.
Epigenetic modifications serve as the mechanism by which innate There are two major classes of T cells that orchestrate CMI in
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immune cells generate immunological memory. There are response to invading pathogens: CD4 T cells and CD8 T cells.
numerous lingering questions about innate immune memory, Antigen presentation by DCs activates T cells. T-cell activation
including the duration of this response, its ability to provide is also driven by cytokines secreted from macrophages and DCs.
protection from other microbes, and whether this type of response In turn, activated T cells secrete cytokines that elaborate the
can be elicited by vaccination. immune response.

LINKING THE INNATE IMMUNE RESPONSE TO
ADAPTIVE IMMUNE RESPONSE KEY CONCEPTS
Adaptive Immunity to Fungal Pathogens
A secondary, but critical, role of the innate immune system is
to amplify the immune response by activating and recruiting • T-cell immunity is critical for fungal host defenses. Patient with advanced
cells of the adaptive immune system, including T and B lym- HIV infection and AIDS are at heightened risk for C. neoformans
infection.
phocytes. The innate immune signaling events that trigger • T-helper 1 (Th1) and Th17 T cell subsets are the most important T
activation of adaptive immunity are complex and may be pathogen cells for control of fungal infection
dependent. This amplification of the immune response is partially • Th2 cells mediate fungal asthma and hyperreactivity.
achieved by secretion of cytokines and ROS that recruit immune • Dectin-1 signaling is required for Th17 immunity.
cells to the site of infection. Additionally, antigen-presenting • Humoral immunity may play a role in antifungal defense but appears
cells (APCs) of the innate immune system use class II MHC to play a supportive role.
molecules on their surface to present pathogen-derived antigens
to I CD4 T cells, resulting in differentiation into effector or
regulatory T cells (Tregs). CD4 T Cells
DCs provide the critical link between the innate and adaptive CD4 T cells are major players in host fungal immunity. The
arms of the immune system. DCs are capable of recognizing critical role for CD4 T cells became overwhelmingly apparent
fungal pathogens similar to macrophages. Endowed with both during the AIDS epidemic. Patients with HIV/AIDS experience
TLRs and CLRs, DCs are activated by components of the fungal loss of CD4 T cells and are extremely susceptible to opportunistic
cell wall. Subsets of DCs provide specialized function. pDCs fungal pathogens, especially C. neoformans infection. Additionally,
produce IFN-α in response to ligands that engage endosomal subsets of CD4 T cells, including Th1, Th2, and Th17 cells, have
TLRs. Although pDCs play a key role in viral infections, their specialized roles in fungal defense (Chapter 16).
role in fungal infections is not fully understood. pDCs are able
to recognize A. fumigatus through engagement of TLR9. When Th1 Cells
A. fumigatus and pDCs are coincubated in vitro, growth of the Th1 cells are a subset of CD4 T cells that play a critical role in
fungus is inhibited, indicating that these cells are capable of controlling fungal infections. After exposure to fungal pathogens,
controlling growth of this mold. A subset of pDCs secretes IL-6 APCs secrete IL-12, which is critical to the maintenance and
and IL-23, the latter of which can serve to prime antigen-specific expansion of Th1 lymphocytes. Mutations in the IL-12 signaling
Th17 lymphocytes. pathway predispose mammals to Candida, Cryptococcus, and
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CD8 DCs possess the unique capacity to cross-present Coccidiomycosis infections. Th1 lymphocytes produce copious
antigens. Cross-presentation of Histoplasma capsulatum antigens amounts of IFN-γ, TNF-α, and granulocyte macrophage–colony