Page 461 - Clinical Immunology_ Principles and Practice ( PDFDrive )

440 ParT ThrEE Host Defenses to Infectious Agents

helminth infection and promotes inflammatory responses and
Helminths and Dendritic Cells increased susceptibility.
DCs are professional antigen-presenting cells (APCs) that play an
essential role in presenting antigen to T cells to initiate immune Helminths and T Cells
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responses. Although the role of DCs in inducing Th1, Th17, Typically, infections with helminths induce a robust Th2 response
and Treg responses is well established, their role in inducing manifested by enhanced expression of IL-4, IL-5, IL-9, IL-10,
Th2 responses has remained relatively unclear. Nevertheless, a and IL-13 in response to live parasites, parasite antigens, or
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series of studies have shown that DCs are required for optimal mitogens. The central player in Th2 immunity is certainly the
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Th2 responses in vivo. Thus in vivo depletion of DCs has been CD4 Th2 cell. It is clear that IL-4Rα, a component of both the
shown to inhibit the induction of Th2 responses to S. mansoni IL-4 and IL-13 receptors, is at the epicenter of Th2 immunity,
or Heligmosomoides polygyrus. Helminth products can prime since IL-4 and IL-13, together or individually, are absolutely
DCs for the induction of Th2 responses by interaction with critical for resistance to most helminth parasites. Recent work
pattern recognition receptors (PRRs), such as Toll-like receptors has reported that the Th2 cell population is heterogeneous,
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(TLRs) and C-type lectin receptors (CLRs). This interaction, containing both IL-5 and IL-5 Th2 cells that express IL-4 and
which depends on TLR and CLR signaling, can promote Th2 IL-13. In addition, IL-4 and IL-13 production is spatially separated,
responses by suppressing antigen presentation, costimulation, with IL-13 expression being marked in tissues and IL-4 expression
and/or expression of Th1-promoting cytokines by directly being pronounced in the lymph nodes within the Th2 cell
interfering with these pathways. DCs that drive Th2 responses compartment. Finally, induction of GATA-3 and downregulation
typically exhibit specialized markers, such as CD301b, PDL2, of T-box expressed in T cells (T-bet) has been shown to be an
and CD11b, and several receptors for the Th2-related cytokines important step in T resistin-like molecule cell differentiation to
IL-4R, IL-13R, IL-25R, TSLP-R, and IL-33R. Additionally, the the Th2 phenotype in helminth infections. Interestingly, chronic
extracellular signal-regulated kinase (ERK) and signal transducer helminth infections are associated with downmodulation of
and activator of transcription 4 (STAT4) pathway upregulates the parasite antigen-specific proliferative responses as well as IFN-γ
costimulatory molecules, CD40, OX40L, and Jagged. Activation and IL-2 production but with intact IL-4 responses to parasite
of the major transcription factors interferon regulatory factor antigens and global downregulation of both Th1 and Th2
4 (IRF4) and KLF4 inhibits IL-12 production and increased responses to live parasites. Finally, the receptor NLRP3 has been
IL-10 secretion. In addition, DCs expressing FcεRIII can induce shown to be a key transcription factor in Th2 differentiation.
murine IgG1-related Th2 responses. These factors typically Although the role of tissue resident memory T (T RM ) cells is
act individually or in concert to orchestrate Th2 responses in well established in viral and bacterial infections, very little is
helminth infections. Although Th2 cell–mediated immunity known about the role of these cells in helminth infections.
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requires IRF4-dependent CD301b CD11b DCs in the mouse, However, it has been shown that tissue-resident Th2 cells can
Langerhans cells are the predominant inducers of Th2 cells ex exert innate (TCR-independent and IL-33–dependent) functions
vivo in humans. The modulation of DC function by helminth upon appropriate stimuli and confer protection against helminth
antigens appears to be generalizable and has been shown to infection. In addition, although multifunctionality (ability to
impair their ability to respond to other infectious stimuli (e.g., produce two or more cytokines) has not been well described in
Mycobacterium tuberculosis). the Th2 cell compartment, helminth infections are known to be
associated with an antigen-dependent enhancement of mono- and
Helminths and Macrophages dual-functional Th2 cells and its reversal after treatment. Of
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Macrophages are the other important class of APCs that can interest, a stable subset of parasite induced T-bet , GATA-3 ,
serve as protective effector cells in bacterial and protozoan Th1/Th2 hybrid T cells has been described to develop directly
infections by their production of nitric oxide and other mediators. from naïve precursors and to play a role in limiting pathological
Helminth interaction with macrophages induces a population inflammation in animal models of helminth infection.
of cells preferentially expressing arginase instead of nitric oxide Recently, a new subset of T cells expressing IL-9 and IL-10,
as a result of increased activation of arginase-1 by IL-4 and but not IL-4 (and therefore different from Th2 cells), has been
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IL-13. These AAMs are characterized by their ability to upregulate described in allergic inflammation and in response to intestinal
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arginase-1, chitinase 3-like proteins 3 and 4 (also known as Ym1 parasites. These cells appear to be under the control of TGF-β
and Ym2, respectively), and RELM-α. These AAMs are known and IL-4 and are dependent on STAT6, GATA-3, IRF4, and PU.1.
to be important in wound healing and have been postulated to Th9 cells have been recently shown to be associated with host
play a potential role in repairing wound damage that occurs protection in Nippostrongylus brasiliensis and Trichuris muris
during tissue migration of helminth parasites. In fact, there infection. Finally, Th9 cells have also been shown to be predomi-
appears to be two distinct populations of AAMs, one derived nantly associated with lymphatic pathology in filariasis. T-follicular
from blood and functioning in an immune regulatory role and helper (Tfh) cells are a subset of CD4 T cells that migrate to
the other derived from tissue-resident macrophages apparently B-cell follicles after activation and promote germinal center
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responsible for much of the fibrosis seen in chronic helminth formation and B-cell isotype switching. These cells, which form
infections. By virtue of the expression of regulatory molecules, an independent lineage of CD4 T cells, have been recently identi-
such as IL-10, TGF-β, and programmed cell death 1 ligand 2 fied to be the predominant IL-4 producing T cells early in
(PDL2), these AAMs may have a predominantly regulatory role helminth infection. In addition, Tfh are major producers of IL-21,
in helminth infections. These antiinflammatory macrophages a cytokine that plays a crucial role in supporting polarized Th2
function through arginase-1, PDL2, triggering receptor expressed responses in vivo.
on myeloid cells 2 (TREM2) and RELM-α to inhibit classic Th17 cells, another subset of CD4 T cells, express the prototypi-
macrophage inflammation and recruitment and T-cell responses. cal cytokine—IL-17. In terms of helminth infections, the role
Similarly, macrophage-derived human resistin is induced by of Th17 cells has been primarily studied in animal models of S.