Page 286 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 18 Regulatory Immune Cells 267

molecules, such as LFA-1) in normal healthy individuals, which (Chapter 63), Tr1 cells specific for desmoglein-3 can be iso-
gives an advantage when engaging with APCs and results in the lated from pemphigus vulgaris–prone but apparently healthy
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prevention of naïve T-cell priming. Interestingly, Foxp3 Tregs individuals, whereas patients with pemphigus rarely have such
have been shown to modify the function of the APC. APCs cells. Collectively, Tr1 cells can be induced by autoantigens as
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cultured with Foxp3 Tregs downregulate CD80 and CD86 via well as foreign antigens as a component of the mechanisms that
a CTLA-4–dependent mechanism and become impaired in their maintain tolerance to both self and nonself. 18
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ability to stimulate T cells. Additionally, CTLA-4–express-
ing Tregs can induce production of the enzyme indoleamine OTHER SUBSETS OF FOXP3 REGULATORY T CELLS
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dioxygenase (IDO), which catalyzes the amino acid tryptophan
to the metabolite kynurenine that represses T-cell responses. Th3 cells were identified in mice during investigations of the
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Importantly, CTLA-4 expression by Foxp3 Tregs has been shown mechanisms of oral tolerance. Oral tolerance has presumably
to be critical for tolerance in vivo, since mice with deletion of evolved to prevent hypersensitivity reactions to food and microbial
this coinhibitory molecule only in Foxp3-expressing cells develop antigens present in the mucosal flora. It was found that mice fed
lethal autoimmunity. Other proposed suppressive mechanisms with myelin basic protein, a neuronal autoantigen, developed T
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that involve close contact between Foxp3 Tregs and target cells cells that preferentially produced TGF-β together with varying
include surface-bound TGF-β, which is inhibitory at a close range; amounts of IL-4 and IL-10. These T cells had suppressive prop-
perforin; and granzyme B, which kills target cells (see Fig. 18.4). 7 erties, mediated by TGF-β, and could prevent the induction
Despite the fact that immunosuppressive cytokines are of experimental allergic encephalomyelitis (EAE), the murine
redundant for suppression in vitro, the in vivo situation seems equivalent of multiple sclerosis (MS) (Chapter 66). Th3 cells can
somewhat different. Recently, the immune suppressive cytokine be identified by their surface expression of latency-associated
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IL-35 has been implicated in Treg-mediated suppression, and peptide (LAP), which binds inactive TGF-β. Recently, LAP Tregs
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both TGF-β and IL-10 expressed by Foxp3 Treg are important have been shown to be induced after oral or nasal administration
in the prevention of IBD in mice. Curiously, adoptive transfer of tolerogenic CD3 monoclonal antibodies. Th3 cells can also
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of IL-10–deficient CD25 Tregs failed to protect against colitis, be generated in vitro if grown in the presence of TGF-β, IL-4,
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although it could inhibit the development of gastritis. Further- and IL-10, although some of them may become Foxp3 iTregs.
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more, although perforin- or granzyme B–expressing Foxp3 Tregs Since the intestinal mucosa has high basal levels of all these
are rare in the spleen, they are abundant in a tumor environment. cytokines, which are upregulated after antigen administration, it is
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Taken together, Foxp3 Tregs can use several different mechanisms conceivable that this particular environment drives the formation
of suppression, and one seems to play a more prominent role of Th3 cells whereas a different setting may produce Tregs of
than another, depending on the local cytokine milieu and the another phenotype. 19,20
strength and type of immune response. 7 In addition to CD4 Tregs, other types of T cells with immu-
nosuppressive properties have also been found; these recognize
Tr1 Cells antigens different from those typically presented to CD4 T cells
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Some Foxp3 suppressive T cells have also been identified. The via MHC class II and may therefore serve to induce tolerance
best characterized are IL-10–secreting Tr1 cells, which have in other settings (see Table 18.1). One example is CD8 T cells
been shown to be present and functional in humans following with TCRs that recognize antigen presented by the mouse MHC
bone marrow transplantation and in response to allergens (see class lb Qa-1 molecule (HLA-E in humans; Chapter 5). Qa-1
Table 18.1). has limited polymorphisms and can present both foreign and
Tr1 cells were initially generated in vitro from CD4 T cells self-peptides. Since Qa-1 peptide complexes on, for example,
rendered anergic by chronic stimulation in the presence of CD4 T cells can bind to both the inhibitory CD94-NKG2 receptor
IL-10, which is a potent negative regulator of inflammation complex and the TCR on CD8 T cells, total loss of Qa-1 does
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and lymphoproliferation. T cells obtained in such a fashion not lead to development of spontaneous autoimmunity, since
produce a unique pattern of cytokines distinct from Th1 or loss of CD94-NKG2 inhibitory signaling is largely compensated
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Th2 cells, with IL-10 as their signature cytokine. In addi- for by loss of TCR signaling. However, specific mutation of
tion, Tr1 cells secrete some TGF-β, interferon-γ (IFN-γ), and Qa-1 leading to its loss of CD94-NKG2, but not TCR binding,
IL-5, but not IL-4 or IL-2. Tr1 cells can be identified on the results in severe lupus-like autoimmunity underpinned by
basis of surface expression of CD49b and LAG-3, but lacking dysregulated Tfh-cell responses. The function of Qa-1–restricted
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Foxp3 expression. In addition, antigenic stimulation with CD8 appears to be largely dependent on perforin expression as
immature DCs (i.e., low levels of costimulatory molecules) or perforin-deficient CD8 T cells fail to mediate the suppression
with DCs pretreated with IL-10/TGF-β confers on naïve CD4 of Tfh cells. 21
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T cells an anergic and suppressive phenotype both in vitro Another subset of regulatory CD8 T cells are CD8 CD28 Tregs,
and in vivo. 17,18 which can suppress immune responses by direct interaction with
Several investigations have shown that Tr1 cells take part in APCs. These cells are generated by multiple rounds of in vitro
the tolerance process in humans. For example, the presence of stimulation with alloantigen and can downregulate costimulatory
Tr1 cells can be correlated with lack of graft-versus-host disease molecules or upregulate the inhibitory immunoglobulin-like
(GvHD) in bone marrow transplantation, and Tr1 cells are also transcript 3 (ILT3) and ILT4 receptors on DCs, leading to the
induced after specific immunotherapy in patients with allergies. impaired activation of effector T cells. 22
Experimental data from a murine model shows that Tr1 cells can Double-negative T cells are a class of αβ TCRs expressing
prevent IBD. Interestingly, Tr1 cells specific for Escherichia coli cells that lack both CD4 and CD8 and make up around 1% of
22
proteins can be isolated from the intestinal mucosa of healthy the TCR αβ cells in mice and humans. Much is still unknown
donors. In pemphigus vulgaris, which is an autoimmune skin about the action of these cells, but it seems that they may be
disorder with circulating autoantibodies against desmoglein-3 able to suppress CD4 and CD8 T cells by taking up antigen–MHC