Biology Reference
In-Depth Information
224
FIGURE 11.1
CD4
+
T-helper cell polarization can be divided into three stages. (I, Polarization) Naïve (“Th0”) cells expressing lymph node homing receptors such as CD62L and
the CD45-RA isoform are exposed to variable cytokine environments during antigen stimulation, which differentially activates various T-cell STAT signaling pathways. (II,
T
CM
) During the T central memory stage of differentiation, the various T-helper subsets differentially express the transcription factors T-bet, ROR-
γ
, FOXP3, and GATA-3
that minimally define the Th1, Th17, Treg, and Th2 subsets, respectively; at this proximal stage of differentiation, the effector CD45-RO isoform is typically expressed
yet cytokine secretion is minimal, consistent with a less differentiated stage. (III, T
EM
) Finally, during the T effector memory stage of differentiation, the various Th subsets
differentially secrete high levels of cytokines and maintain differential transcription factor expression. The term “Enhanced Plasticity Zone” indicates that significant subset
interconversion may occur
in vivo,
for example with Treg cells converting to Th17 cells under the influence of the inflammatory cytokine IL-6; as described in the text, Th1
and Th2 cells also possess differentiation plasticity and T cells with mixed transcription factor expression have also been observed.
in which donor memory T cells carry long histories of cytokine experience
and are thus less amenable to marked Th1/Th2 polarization.
Subset polarization occurs through T-cell activation in the context of a spe-
cific cytokine milieu that results in differential phosphorylation of signal
transducer and activator of transcription (STAT) proteins
[5]
. For Th1 polar-
ity, proximal STAT1 and more distal STAT4 activation occurs via interferon-α
(IFN-α) and interleukin-12 (IL-12), respectively; for Th2 polarity, STAT6
activation occurs via IL-4 receptor signaling. When considering the bench-
to-bedside implications of this STAT biology, the post-transplant Th1/Th2
balance would predictably be determined by both prior polarization history
of the predominantly memory donor T cells and their exposure to STAT-
activating cytokines in the host, which may be influenced by the intensity
and type of pretransplant conditioning (see Chapter 8). These unpredict-
able and relatively fixed donor and host factors do not offer the transplant
practitioner significant power to control the post-transplant Th1/Th2 bal-
ance; to overcome this limitation, we have utilized
ex vivo
manufacturing
of donor CD4
+
T cells to control STAT activation through an extracorporeal
approach (specifically, addition of IL-4 to promote Th2 differentiation).
It is important to recognize that polarized T-helper cells exist in various states
of differentiation
[6]
, including a proximal “central memory” (T
CM
) state
whereby polarization is reflected primarily by expression of the canonical
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