Biology Reference
In-Depth Information
engineering to control the number of adoptively transferred T-bet
+
cells
represents a novel approach to control T-bet expression post-transplant.
Induction of T-bet in Th1 cells is a tightly regulated process that occurs in
a two-step process. First, nonpolarized CD4
+
T cells respond to antigen in
a cytokine microenvironment replete with either IFN-α or IFN-γ for activa-
tion (phosphorylation) of STAT1 transcription factor, which results in rapid
T-bet upregulation
[21]
. And second, after cessation of T-cell receptor sig-
naling, a positive feedback loop is created whereby T-bet promotes expres-
sion of the IL-12 receptor β2 subunit, which confers Th1-cell sensitivity to
IL-12, thereby further driving T-bet expression and IFN-γ secretion
[22]
. As
such, T cell expression of IL-12R β2 can be considered a legitimate surface
marker for a T-bet-driven, Th1-type cell. This complex and tightly regulated
biology probably reflects the narrow “therapeutic window” of T-bet: that
is, insufficient T-bet leaves the host susceptible to multiple infections (for
example,
Mycobacterium tuberculosis
[23]
), whereas overabundant T-bet
can promote autoimmune diseases such as Crohn's disease, which shares a
common pathogenesis with GVHD
[24]
.
At the transcription factor level, a great deal is now understood with respect
to the interrelationship and delicate balance between the CD4
+
functional
T-helper cell subsets. In a theme that is played out again in the discussion of
the contributions of T-cell subsets in GVHD, a deficiency in one potentially
pathogenic subset (such as T-bet
+
Th1 cells) can result in a compensatory
increase in a different CD4
+
T-helper subset that manifests an alternative
mechanism of pathology. For example, in a murine model of Crohn's dis-
ease, genetic deficiency of T-bet and STAT6 abrogates Th1- and Th2-medi-
ated pathology, but sets off an exuberant Th17-mediated colitis
[24]
. As
such, T-helper cell balance, including representation from T-bet
+
Th1 cells,
maintains homeostasis.
226
The molecular basis for this T-helper subset cross-regulation is becoming
increasingly well defined at the transcription factor level. In the case of
T-bet, a promotional effect is exerted (as described above, in part through
an upregulation of IFN-γ and IL-12Rβ2) in concert with multiple inhibitory
effects. Specifically, T-bet, together with a second transcription factor asso-
ciated with Th1 cells, Runx3, works cooperatively to inhibit IL-4 production
by interaction with the
Il4
gene silencer locus
[25]
. And, phosphorylated
T-bet interacts with GATA-3 in Th1 cells to limit GATA-3 interaction with the
Il5
and
Il13
promoters
[26]
. In a similar inhibitory manner, T-bet directly
prevents Th17 cell differentiation through binding and subsequent neu-
tralization of the effects of Runx1, a transcription factor that promotes the
canonical Th17 transcription factor ROR-γt. And, in the reverse context,
fully committed Th17 cells are converted to Th1 cells through STAT1- and
STAT4-mediated induction of T-bet, which induces epigenetic changes that
downregulate ROR-γt expression
[27]
.
It should be noted that the vast majority of research regarding transcription
factor control of T-cell differentiation focuses on the CD4
+
T-cell subsets
and that substantial differences may be discovered at the level of CD8
+
T cells
as further research is performed. As one example, in CD8
+
T cells, T-bet inter-
acts with an additional transcription factor, eomesodermin, which helps tone
CD8 cell effector function
[28]
. And, most recently, using an elegant model
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