Page 285 - Clinical Immunology_ Principles and Practice ( PDFDrive )

266 ParT TwO Host Defense Mechanisms and Inflammation

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in multiple organs, resulting in early death. Moreover, genetic
deficiencies of CD25 in humans generate a comparable clinical and
pathological pattern. It is now known that IL-2–deficient animals Cell contact–dependent Effector
mechanisms :
have substantially reduced, although not completely depleted, -Membrane TGF-β T cell
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numbers of Foxp3 T cells and that disease can be prevented -Consumption of IL-2
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by adoptive transfer of normal Foxp3 Tregs (see Table 18.2). -Granzyme/perforin
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In addition to antigen recognition and cytokines, Foxp3 Tregs -cAMP
require appropriate interactions with antigen-presenting cells Release of
(APCs) for their function and survival. Several molecules of cell immunosuppressive
adhesion and costimulation are important for function and FOXP3 + IL-10 substances
homeostasis of Tregs, including CD18/CD11a, GITR, CD28, and Treg TGF-β (IL-10, tryptophan
CTLA-4. IL-35 catabolites)
-low CD80/CD86
Effector CD4 T cells differentiate into various subpopulations, expression
such as Th1, Th2, Th17, and Tfh, in response to specific stimula- Cell contact–dependent
mechanisms :
tion and cytokine milieus (Chapter 16). It has become clear that -CTLA-4 dependent CD80/86
Tregs mirror this process to some extent and can also differentiate downmodulation
in response to the same stimuli into a subpopulation specialized -Granzyme/perforin
to control the matching effector population. As a result, Tregs
express transcription factors linked to these fates, such as T-bet APC
(Th1), RORγt (Th17), and BCL6 (Tfh), and this allows Tregs to
gain expression of relevant chemokine receptors, such as CXCR5,
in the case of T-follicular regulatory (Tfr) cells, enabling these +
cells to traverse to the germinal center, where they are able to FIG 18.4 Proposed Suppressive Mechanisms of Foxp3
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suppress T-follicular helper (Tfh) cells and the germinal center Regulatory T Cells (Tregs). Foxp3 CD25 Tregs can inhibit many
reaction. Similarly, expression of CCR6 and CXCR3 allows a different types of effector cells and can also suppress immune
similar process to occur for Th17-Tregs and Th1-Tregs, respec- responses at multiple stages, including the initial priming in the
tively. This process lets Tregs respond to the environment and lymph node and effector actions at the site of inflammation.
specifically travel to and suppress Th1, Th2, Th17, and Tfh-cell The precise mechanism is not known, but numerous theories
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responses. Further to the development of Tregs that specifically have been proposed, and it is likely that Foxp3 CD25 Tregs
mirror effector T-cell subsets, it has also been recently demon- suppress by several different mechanisms. In vivo Tregs can
strated that Tregs travel to nonlymphoid sites, such as skin, adipose act in a cell contact–dependent manner by competing directly
tissue, and skeletal muscles, to suppress inflammation. Tregs for stimulatory ligands on the antigen-presenting cell (APC), by
from these sites may represent specialized subtypes of Tregs with absorbing essential growth factors, such as interleukin-2 (IL-2),
adapted transcriptional signatures, such as adipose tissue Tregs, or by directly transmitting an as-yet uncharacterized negative
expressing the transcription factor peroxisome proliferator- signal to either the T cell or the APC. Alternatively, Tregs can use
activated receptor-γ (PPAR-γ), which regulates fatty acid long-range suppressive mechanisms by means of the cytokines
metabolism and allows their homeostasis and survival in this IL-10, IL-35, and transforming growth factor-β (TGF-β).
environment. 15
Another important aspect of Treg responsiveness to the
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environment is that Tregs are affected by the microbiota (Chapter Foxp3 Tregs likely suppress by multiple mechanisms, including
14). Recently, it has been demonstrated that certain commensal both soluble and cell surface–bound mediators (Fig. 18.4). In
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organisms, such as Clostridium spp. present in the gut, have large vitro studies have shown that Foxp3 Tregs need direct cell-to-cell
effects on Treg differentiation in these environments. In some contact with responder cells and that suppression does not occur
cases, this may be indirect via induction of TGF-β production if Tregs are separated from effector T cells by a semipermeable
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leading to induction of Tregs from naïve T cells, whereas in other membrane, even if this allows the passage of soluble factors.
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cases, microbial metabolites, such as short-chain fatty acids, Moreover, Foxp3 CD25 Tregs are not prominent producers of
directly induce Treg proliferation. 11 either IL-10 or TGF-β in vitro. These features are quite different
from those of Tr1 or Th3 cells, which primarily rely on soluble
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Suppressive Function of Foxp3 Tregs immunosuppressive cytokines, such as IL-10 and TGF-β, for
The standard assay to analyze the suppressive function of Tregs is their inhibitory function.
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to coculture purified cell fractions of T cells with Tregs and then Although Foxp3 Tregs have been shown to suppress effec-
measure the proliferative response upon antigenic stimulation tor T cells under APC-free conditions in vitro, presumably by
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in the presence of APCs. Such assays show that freshly isolated absorbing IL-2, it is reasonable that Foxp3 Tregs in vivo control
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Foxp3 CD25 Tregs are not able to suppress T-cell responses in immune responses also by regulating APCs. Indeed, by using
vitro unless they are first stimulated via the TCR. Once activated, two-photon laser-scanning microscopy, it has been shown in vivo
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they suppress other CD4 and CD8 T cells, irrespective of their that although there are limited contacts between Foxp3 Tregs
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antigen specificities. Foxp3 Tregs can inhibit proliferation and and effector T cells, stable interactions exist between Foxp3 Tregs
cytokine production of naïve T cells. They can also suppress the and dendritic cells (DCs) during ongoing suppression in lymph
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function of already differentiated Th1 and Th2 cells in vitro and nodes. One way that Foxp3 Tregs regulate immune responses
have been shown to reverse ongoing immunopathology, such as may be through competition with effector T cells for access
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colitis, in vivo. In addition to suppressing T-cell function, Foxp3 to APCs. Foxp3 Tregs have, relative to conventional T cells, a
Tregs are also able to suppress B cells, NK cells, and NKT cells. more activated phenotype (e.g., high expression of adhesion