4 Immune Tolerance 51

Differentiation IL-12 IL-4 IL-4 TGF-β, IL-6 TNF-α, IL-6

cytokines: TGF-β IL-21, IL-23

Th2 Th2 Th9 Th17 Th22

Effector IFN-γ IL-4, IL-5, IL-13 IL-9 IL-6, IL-8, IL-17A IL-22
cytokines: IL-25, IL-31, IL-33 IL-17E, IL-22, IL-26

Functions: Intracellular Helminths, Mucus Extracellular pathogens, Tissue

pathogens, allergic inflammation, production, chronic neutrophilic inflammation.
apoptosis of IgE, tissue inflammation, Tissue healing,
tissue cells, chronic eosinophilic inflammation antimicrobial immune defense to
delayed-type inflammation peptides extracellular
hypersensitvity bacteria,
tissue protection

Treg

Figure 4-6 Antigen presentation by dendritic cells to naïve T cells and other factors (e.g., innate immune response substances, vitamins, cyto-
kines in the environment) induce the T cells to produce interleukins and to differentiate into Th1, Th2, Th9, Th17, or Th22 cells. These T cell
subsets can promote different types of inflammatory responses based on their respective cytokine profiles, responses to chemokines, and
interactions with other cells. Treg cells directly or indirectly suppress all other effector T cell subsets. IFN-γ, Interferon-γ; IgE, immunoglobulin
E; IL, interleukin; TGF-β, transforming growth factor-β; Th, helper T cell subset; TNF-α, tumor necrosis factor-α; Treg, regulatory T cell.

Direct and indirect

suppressive effects on
mast cells, basophils,
and eosinophils
Suppression of
T cell migration to tissues,
remodeling in tissues
DC
Mast cell Basophil Eosinophil

Suppression of
inflammatory DC
Induction of IL-10–
Suppression of Th17 TReg producing DC
effector Th17 cells

B cell

Induction of IgG4
Suppression of Th2 Suppression of IgE
Th1
effector Th1 cells
Suppression of
effector Th2 cells
Figure 4-7 Immune deviation toward a Treg cell response is an essential step in allergen-specific immunotherapy and natural allergen exposure
of nonallergic individuals. Treg cells use multiple suppressor factors, which influence the final outcome of specific immunotherapy. Treg cells
suppress proliferation, tissue infiltration, proinflammatory cytokine production, and injury or apoptosis of epithelial cells by Th1 and Th2 cells.
Interleukin-10 (IL-10) induces immunoglobulin G4 (IgG4) and transforming growth factor-β (TGF-β) induces IgA from B cells as noninflammatory
immunoglobulin isotypes. Both IL-10 and TGF-β suppress IgE production. These two cytokines directly or indirectly suppress effector cells of
allergic inflammation, such as mast cells, basophils, and eosinophils. Treg cells use IL-10, TGF-β, cytotoxic T lymphocyte–associated protein 4
(CTLA4), programmed cell death 1 protein (PDCD1), and histamine H2 receptor in these functions. DC, Dendritic cell; Th, helper T cell subset;
Treg, regulatory T cell.

directs the peripheral conversion of effector T cells into FOXP3+
Treg cells.81 However, in the presence of IL-6, TGF-β promotes
the generation of Th17 from naïve T cells.82 Retinoic acid also
plays a key role in the balance of inflammatory Th17 cells and
suppressive Treg cells by inhibiting the formation of Th17 cells
and enhancing the expression of FOXP3 through a STAT3/
STAT5 independent signaling pathway.83
Immune Suppression by Regulatory T Cells
Treg cells suppress other cells through several proposed mecha-
nisms, such as cell contact–dependent mechanisms, which have
been observed in most in vitro studies, and cytokine-dependent
mechanisms (Fig. 4-7). Suppression and regulation may be tar-
geted at effector T cells, B cells, or APCs to reduce the ability of
APCs to prime T cells by modulation of costimulation and