Th1/Th2 and Tc1/Tc2 cells: biology, experimental models and clinical translation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 225

IL-2, which activates STAT5, works in concert with IL-4 for Th2-cell induc-
tion [43] . Interestingly, the combination of GATA-3 plus STAT5 upregulates
the T1/ST2 receptor, which transmits signals for a cytokine recently associ-
ated with Th2 cell function, IL-33 [44,45] . In a further example of the com-
plexity of Th2 cell regulation, DEC2 transcription factor and subsequent
JunB transcription factors have been found to promote Th2-cell lineage
commitment [46] .

In addition, just as T-bet confers Th1-cell commitment by promotion of the
Th1 lineage and inhibition of the Th2 lineage, GATA-3 similarly protects
its allegiance to the Th2 phenotype at multiple levels. At level 1, GATA-3
inhibits T-cell expression of IL-12Rβ, thereby limiting Th1 polarization
potential [36] . And, as a functional backup at level 2, GATA-3 suppresses
T-cell capacity to signal via IL-12Rβ through inhibition of STAT4 expression
[47] . GATA-3 also negatively regulates the Th1-cell transcriptional cofac-
tor Runx3 [48] , which is a critical determinant of the magnitude of Th1-cell
effector function [49] .

In sum, this deeper dive review of transcription factor events that determine
T-helper cell fate highlights several principles of relevance for bench-to-
bedside considerations in allogeneic HCT. First, the field has transitioned
from an initial era of Th1/Th2 biology that was predicated upon cytokine
cross-regulation (IL-4 vs IFN-γ) to the current era, which is dominated by
transcription factor competition (GATA-3 vs T-bet). As such, translational
efforts would probably benefit from a shift toward this new definition, with
careful measurement of allograft T-cell content and post-transplant T-cell
reconstitution at a transcription factor level; ultimately, this information
may be utilized to engineer allograft T-cell content for a specific post-trans-
plant outcome. Second, in contradistinction to initial thoughts that T-cell
subsets were relatively stable in phenotype, the current literature suggests
a great deal of functional plasticity that is facilitated by single-cell expres-
sion of multiple transcription factors, the balances of which are not fixed.
Translational efforts must therefore embrace this concept of plasticity, with
efforts to restrict the in vivo phenotype flexibility of optimally balanced
allograft T cell subsets; or, in the case of post-transplant complication
mediated by a specific T-helper subset, one may utilize an understand-
ing of plasticity mechanisms (such as specific STAT activation pathways)
to administer cytokines, cytokine inhibitors, or pharmacologic agents that
induce T-helper differentiation away from the pathogenic subset. And
finally, increasing evidence indicates that each of the T-helper subsets can
be pathogenic in its own right; and, deficiency of any one given subset,
including the Th1 subset, can result in pathology mediated by an alterna-
tive subset. From a translational standpoint, it is therefore apparent that
allograft T-cell content may best include representation from a diversity of
subsets, including the Th1 subset.

228

CD8 cell biology and the Tc1/Tc2 subsets

As previously detailed, although functionally defined CD4 + T-cell subsets
were the first to be described and have been characterized the most exten-
sively, a similar pattern of cytokine polarization can occur within CD8 +
T cells. Perhaps most noteworthy was the description by Mosmann and