Th1/Th2 and Tc1/Tc2 cells: biology, experimental models and clinical translation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 226

colleagues of the existence of murine CD8 + T-cell subsets, the Tc1 and Tc2
populations, which each mediated cytotoxicity yet differentially secreted
Th1- vs Th2-type cytokines, respectively [50] . The Tc1 and Tc2 subsets, in
a manner analogous to their CD4 + Th1/Th2 counterparts, are generated
through CD8 + T-cell exposure to antigen in a cytokine microenvironment
that contains polarizing cytokines such as IL-12 or IL-4, respectively [51] . It
is important to note that the Tc1 and Tc2 subsets differ not only with respect
to cytokine secretion but also in terms of: (a) cytotoxic mechanism, with
increased utilization of Fas-mediated cytolysis in Tc1 cells [52] ; (b) chemo-
kine receptor expression [53] ; and (c) most importantly, in vivo protection,
with Tc1 cells mediating more effective anti-tumor immunity relative to the
Tc2 subset [54] .

Experimental transplantation models evaluating the
Th1/Th2 paradigm
Overview

In parallel with research efforts that have elucidated this increasingly mech-
anistic understanding of Th1/Th2 regulation, researchers have investigated
the potential role of this complex biology in the modulation of transplan-
tation responses. As with most research efforts, experimental modeling
has been relatively robust, with a relative paucity of clinical correlative
and interventional studies. Nearly all experimental studies have been per-
formed in murine models owing in great part to the relative abundance of
reagents for interrogation of T-cell biology and the availability of T cells
genetically deficient in key molecules that dictate Th1/Th2 biology. And,
recent advances in the development of human-into-mouse xenogeneic
transplantation models have offered the possibility of evaluating human
T-cell subsets in vivo as somewhat of a bridge to clinical trials; in this regard,
we have recently characterized the ability of ex vivo manufactured human
CD4 + Th1 cells to mediate lethal xenogeneic GVHD [55] . Finally, from a
bench-to-bedside perspective, it is important to differentiate whether an
experimental model addressing the Th1/Th2 paradigm holds value primar-
ily by illustrating the natural history of transplantation biology (specifically,
evaluation of the effects of administering nonpolarized, unmanipulated
donor T cells) or by offering principles and insights essential for purposeful
immune modulation (specifically, evaluation of the effects of administering
ex vivo -manipulated and cytokine-polarized donor T cells).

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Investigation of the Th1/Th2 paradigm in experimental
transplantation (natural history models)

In murine natural history transplantation models, the biology of acute
GVHD has, in general, been characterized as a process whereby unma-
nipulated donor T cells primarily adopt Th1-type differentiation. That is,
CD4 + T-cell production of IL-2 [56] and expression of CD40 ligand [57] play
key roles in GVHD natural history; importantly, CD40 ligand primes anti-
gen-presenting cells (APCs) for IL-12 production, which then propagates
Th1-driven acute GVHD [58] . Th1 cells also preferentially lyse targets via
Fas ligand, which contributes to skin, gut, and liver GVHD [59,60] . CD8 + T