Th1/Th2 and Tc1/Tc2 cells: biology, experimental models and clinical translation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 224

incorporating selective add-back of the endogenously expressed microRNA
miR-29, it was determined that T-bet and eomesodermin also cooperate to
induce CD4 + Th1 differentiation [29] . Combined loss of T-bet and eome-
sodermin results in more profound CD8 cell immune defects relative to
single gene deletion; such transcription factor cooperativity is based partly
upon dual upregulation of CD122 (IL-15 receptor β-subunit), which confers
responsiveness to the key CD8 cell growth factor, IL-15 [30] . The expression
ratio of these transcription factors also controls CD8 cells in terms of the
balance between fully differentiated T EM cells (higher T-bet/lower eomeso-
dermin) and self-renewing T CM cells (lower T-bet/higher eomesodermin)
[20] . In addition, CD8 + T cells express a newly discovered transcription fac-
tor, Blimp-1, which appears to be essential for cytotoxic T-cell secretion of
IL-10 at a late stage of differentiation; this phenomenon of late IL-10 secre-
tion within Th1/Tc1 cells thus serves as an autocrine safeguard against auto-
immunity [31] . Certainly, these recent findings indicate that further research
will identify additional complexities in the role of transcriptional factors in
the determination and regulation of Th1/Tc1 cell fate.

GATA-3 and Th2 differentiation: a deeper dive

227

Just as T-bet controls immunity via its action on multiple cell types, GATA-3
mediates profound immune regulatory effects well beyond the CD4 + Th2
subset. Most notably, in the thymus, GATA-3 induces ThPOK, which directs
thymocyte differentiation to the CD4 + single-positive lineage [32] ; and,
reminiscent of T-bet expression in Treg cells, GATA-3 expression in Treg
cells can stabilize FOXP3 expression and enhance Treg cell homeostasis
in vivo [33] . With respect to Th2-cell differentiation, GATA-3 is upregulated
by two pathways, one that is IL-4/STAT6 dependent [34] and one mediated
by low-dose antigen exposure in an IL-4-independent manner [35] . The net
result of GATA-3 upregulation mandates Th2-cell differentiation even in the
setting of Th1-polarizing conditions [36] , with subsequent synchronized
promotion of transcription at the Th2 gene locus, which includes IL-4, IL-5,
and IL-13 [37] . Although IL-10 was initially classified as a Th2-derived cyto-
kine that cross-regulated Th1 cells [38] , IL-10 is not a component of the Th2
gene locus and is increasingly viewed as a downregulatory cytokine pro-
duced by a myriad of immune cells, including, as discussed, late-stage Th1
cells capable of self-regulation [31] .

GATA-3 modulates the T-cell cytokine phenotype largely through epigen-
etic modification, including alterations in histone methylation (H3K4 locus)
and acetylation (H3K14 locus) at multiple sites within the Th2 gene [39] .
GATA-3 binds to the conserved noncoding sequence 1 site to direct IL-4
production [40] and to the CGRE site to promote transcription of the distal
effector Th2-cell cytokine, IL-13 [41] . In addition to its effects on epigenetic
modulation, GATA-3 directly promotes Th2-cell cytokine production, in
particular downstream IL-5 and IL-13 [42] .

In addition, reminiscent of the multitranscription factor regulation that
occurs in Th1 cells, GATA-3 operates in conjunction with other transcrip-
tion factors to promote Th2-cell differentiation. That is, GATA-3 cooper-
ates with STAT5 transcription factor to promote Th2 differentiation [35] ;
this molecular interaction thus accounts for the seminal observation that