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also expressed both IL-21 and IL-22, so it remains uncertain whether these
cytokines might contribute to some of the pathological manifestations
observed under these conditions. The ability of
in vitro
-polarized Th17
cells to induce lethal GVHD and, more precisely, augment pathology in the
lung relative to Th1 cells has been confirmed by Iclozan and colleagues
[60]
.
They also noted instability of the cytokine profile
in vivo
after transfer, with
increased production of both IFN-γ and TNF-α but, as in Carlson et al.
[59]
,
they observed that IFN-γ was not required for GVHD mediated by Th17
cells. In this report, the authors parenthetically noted that skin pathology
was not increased, but this may have been attributable to different murine
models being employed.
While instructive, there are a few potential caveats to the use of
in vitro
-
generated cells to study the Th17 response in GVHD. First of all, the cytokine
combination used for Th17 polarization
in vitro
might not resemble the
actual cytokine milieu that induces this T-cell subset differentiation
in vivo
after allogeneic BMT. Therefore, these
in vitro
highly manipulated Th17
cells may not truly represent this cell population when generated under
pathophysiological conditions. Second, after
in vitro
stimulation, Th17
cells are highly activated and might have altered survival and migration
patterns distinct from those of naïve T cells, which differentiate into Th17
cells
in vivo.
These alterations might be responsible, in part, for their unique
pathogenic potential in these studies. Finally, in several other reports, only
small numbers of Th17 cells have been identified in mice with acute GVHD,
raising the question as to how significant a contribution these cells may
make during acute GVHD in comparison to Th1 cells, which are typically
present in larger numbers
[58,61]
.
277
The prior studies raised the interesting question as to whether various
T-helper populations (i.e., Th1, Th2, Th17) might have unique and nonre-
dundant roles in mediating GVHD pathology in specific target organs. To
address this question, Yi and colleagues
[62]
used cytokine double-knock-
out donor T cells (IFN-γ
−/−
IL-4
−/−
and IFN-γ
−/−
IL-17
−/−
) to delineate the rela-
tive contributions of Th1, Th2, and Th17 cells to the pathogenesis of acute
GVHD and to study how different subsets of CD4
+
T cells induced GVHD
in different target organs. Using a standard B6 → Balb/c GVHD model, they
reaffirmed that acute GVHD in this setting is primarily a Th1-mediated
event. In the absence of the Th17-associated cytokine IL-17, or Th2-associ-
ated cytokine IL-4, Th1 differentiation was further augmented, which led to
an exacerbation of tissue damage in the gut and liver. In contrast, absence
of IFN-γ in CD4
+
T cells resulted in enhanced Th2 and Th17 differentiation
and exacerbated tissue damage in both the lung and the skin. The absence
of both IL-4 and IFN-γ resulted in increased Th17 differentiation and pref-
erential tissue damage in skin, whereas absence of both IFN-γ and IL-17 led
to further augmentation of Th2 differentiation and lung damage. The tissue
specificity mediated by Th1, Th2, and Th17 cells was attributed, in part, to
the differential expression of chemokine receptors. Th1 cells, which prefer-
entially cause GVHD in gut and liver, expressed high levels of the gut-hom-
ing receptors α4β7 and CCR9 as well as the liver-homing receptors CCR5
and CXCR6. In contrast, Th2 and Th17 cells, which preferentially caused
GVHD in skin and lung, expressed high levels of lung- and skin-homing
molecules CCR3, CCR4, and CCR6. In addition, the expression of ligands for
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