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FIGURE 13.1
Differentiation of CD4 + T-cell lineages. The cyto-
kines associated with arrows are dominant cytokines
involved in the specification of each of the indicated
lineages. The cytokines listed below each cell type
are key effector or regulatory cytokines produced by
differentiated cells of that lineage or, in the case of
nTregs, a contact-dependent mechanism of suppres-
sion. Tn, naïve postthymic CD4 T-cell precursors; Tp,
thymic precursors. Dotted lines represent less well
defined lineage relationships. (From: Weaver C T et al.
Immunity 2006; 24: 677.)
during T-helper cell differentiation can mediate significant phenotypic
shifts related to cytokines expressed by Th17 cells.
An important aspect of Th17 cell differentiation is the relationship that these
cells have with regulatory T cells (Tregs). Tregs are critical for the mainte-
nance of immunological homeostasis and self-tolerance in vivo [43] . These
cells have been classically defined as being CD4 + and expressing the tran-
scription factor FOXP3 [44] . This population of cells comprises two major
subsets, which have been termed natural (nTregs) and induced (iTregs),
based on the unique ontological and developmental characteristics that are
specific for each cell population [45] . nTregs are generated in the thymus
and then migrate to the periphery to regulate immune responses, whereas
iTregs derive from the conventional T-cell pool and undergo conversion in
the periphery after encounter with antigen in the presence of TGF-β [46,47] .
Work by Kuchroo and colleagues [23] established that IL-6 is a pivotal cyto-
kine that controls the differentiation decision of naïve T cells to become
either iTregs or Th17 cells. In the presence of IL-6, T cells differentiate into
Th17 cells, whereas in the absence of this cytokine the development of iTregs
is fostered [23] . Moreover, FOXP3 itself is able to associate with ROR-γt and
inhibit ROR-γt transcriptional activation [24] . Thus, IL-6 acts as a potent
proinflammatory cytokine through promotion of Th17 differentiation and
inhibition of Treg differentiation, indicating that this cytokine alters the bal-
ance between effector and regulatory T cells ( Figure 13.1 ).
274
Role of IL-17 and Th17 cells in preclinical models of
acute graft-versus-host disease
The critical role that Th17 cells, and IL-17, more specifically, play in inflam-
mation was a natural impetus for the subsequent inquiry into the role that
these cells play in graft-versus-host disease (GVHD) biology. Prior studies
had clearly demonstrated that Th1 cells can mediate pathological damage in
experimental models of GVHD [48,49] . Specifically, cytokines that are typi-
cally associated with Th1 cells, such as IFN-γ, TNF-α, and IL-2, were found
to be increased in the serum and target organs of GVHD recipients [49] . This
is in contrast to studies examining the role of Th2 cells, which have been
largely, but not exclusively, shown to have a more protective phenotype in
GVHD biology. This conclusion is supported by studies demonstrating that
 
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