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therefore of the Th1 development (Farrar 2002).
Another transcription factor that is specific for Th2
cells is c-MAF, which is also responsible for regulating
IL-4 synthesis through the activation of the IL-4 promoter
( Ho 1996). Once GATA-3 production reaches a
certain threshold, its own gene expression is auto-activated,
hence stabilizing the Th2 phenotype through an
intrinsic positive-feedback loop (Farrar 2002). As Th2
cells mature, they produce increasing levels of IL-4,
which generates a paracrine loop and induces neighboring
naive T cells to develop into Th2 cells.
IL-6, another cytokine released by macrophages, mast
cells and pulmonary DCs during the early stages of a
Th2 response, induces the Th2 phenotype through the
up-regulation of IL-4 and inhibition of STAT1 phosphorylation,
thereby preventing IFN-γ gene expression
(Dodge 2003, Detournay 2005). In humans, IL-11
released by myeloid cells acts directly on T cells to stimulate
IL-4 and IL-5 expression, while simultaneously
inhibits IFN-γ production. IL-11 also suppresses IL-12
secretion and therefore also contributes to Th2 differentiation
through this indirect mechanism ( Curti
2001). Activated DC2 may induce Th2 differentiation
indirectly via the secretion of IL-10, which then inhibits
IL-12 synthesis at mRNA level and thus the Th1 pathway
(Koch 1996). IL-10 also down-regulates IL-12β2R
expression (Romano 2005), suggesting that the development
of the Th2 phenotype would be the default
pathway, occurring spontaneously in the absence of IL-
12, but this is a point of controversy (Langenkamp
2000, Maldonado-López 2001). Whether DC2 secrete
other soluble factors that promote Th2 cell development,
remains unknown. Mast cell degranulation and
mediator release can reduce the capacity of DCs to
induce Th1 cells and promote the development of IL-4secreting
T cells (Mazzoni 2006) suggesting that mast
cells may have a role in the development of the antigenspecific
Th2 cells in mast cell-related disorders, such as
atopy. Several coreceptors are implicated in the activation
and the reinforcement of the Th2 phenotype.
Following Th cell activation, the costimulatory molecule
ICOS is up-regulated and is retained on both effector
and memory cells (Hutloff 1999). Its ligand (ICOS-
L), is expressed on most APCs, including DCs, B cells,
activated monocytes, fibroblasts and endothelial cells
(Wassink 2004). ICOS participates in the regulation of
T-cell activation by supporting the release of many
cytokines (Okamoto 2004). ICOS –/– T cells are selectively
deficient in IL-4 production (Nurieva 2005), and
inhibition of ICOS activity results in the arrest of Th2
cell-mediated allergic airway responses without change
of Th1-mediated IFN-γ secretion (Coyle 2000).
Regulation of Th1/Th2 responses
An impressive series of in vitro and in vivo data
obtained in both experimental animals and humans,
have shown that Th1 and Th2 responses are mutually
regulated in a process known as re-direction or immune
deviation. IL-12, IL-18, IFN-γ and IFN-α not only
G. Del Prete - The complexity of the CD4 T-cell response
favour the development of Th1 cells, but also inhibit
the development of Th2 cells. Likewise, a number of
pathogen products or even synthetic adjuvants, which
are agonists of TLRs present on DCs and/or NK cells
and are able to induce the production of IL-12 and/or
IFNs by cells of the innate immunity, promote the shifting
of Th2 responses to the less polarized Th0, or even
to the Th1 polarized profile and effector functions (Erb
1998, Klinman 2004, Mohamadzadeh 2005, Revets
2005, Amedei 2006, Filì 2006). For example, the
Neutrophil Activating Protein (HP-NAP) of
Helicobacter pylori, a TLR2 agonist, is able to redirect
to Th1 allergen-specific Th2 responses (Amedei 2006)
(Figure 1). Even established human Th2 responses can
be shifted, at least in vitro, to a Th1 profile by antigenstimulation
in the presence of IL-12 (Annunziato
2001) and this phenomenon seems to be due to the IL-
12-induced long-term persistence of the β2 chain of the
IL-12R, which is transiently expressed by Th2 cells
after TCR stimulation alone (Smits 2001). Conversely,
IL-4 inhibits Th1 cell development and shifts Th1
responses to a less-polarized phenotype, even if established
Th1 responses seem to be less susceptible to redirection
than Th2 responses (Ghoreschi 2003,
Skapenko 2004).
Fig. 1. Re-direction to Th1 of mite allergen-specific CD4 Th2
cells induced by H. pylori Neutrophil Activating Protein (HP-
NAP). Mite allergen-induced T-cell lines were generated in
the presence of medium alone, HP-NAP or IL-12. T-cell
blasts of each line were then cloned and allergen-specific T
cell clones were stimulated for 48 h with medium or the
allergen in the presence of irradiated autologous APC.
Culture supernatants were then collected and assayed for
their IFN-γ and IL-4 content. Clones able to produce IFN-γ,
but not IL-4, were categorized as Th1, clones producing
IL-4 but not IFN-γ were coded as Th2, whereas clones producing
both IFN-γ and IL-4 were categorized as Th0. Results
represent mean percent proportions (+ SD) of clones with
the indicated cytokine profile obtained from series of three
T-cell lines for each condition.