Biology Reference
In-Depth Information
GVL EFFECTS
There are two elements to consider with respect to the anti-tumor effects
mediated via TNFR signaling: the direct induction of apoptosis in the target
leukemic cell and the role of TNF in promoting adaptive immune responses.
TNF is capable of direct killing through TNFR1 only, and preclinical data
suggest that the role of TNF/LTα3 in tumor apoptosis is dependent on the
TNFR expression profile of the tumor
[37]
. Direct TNFR-mediated apopto-
sis is likely to be dictated by both TNFR expression and the quantity of TNF
and LTα3 produced by the donor cytotoxic T cell. Importantly, perforin and
granzyme are well established as the dominant cytotoxic pathways involved
in GVL effects post-transplant
[65]
.
The roles of TNF in T-cell maturation and costimulatory molecule expres-
sion also have an impact on GVL
[35]
. The role of TNF in GVL has been
studied using several conditioning regimens (i.e., combination TBI and
chemotherapy), various TNF-neutralizing regimens, and multiple mouse
strain/leukemia combinations
[38,50,66-68]
. Some of these studies report
that soluble TNF makes an important contribution to tumor clearance
[38,66]
, while others have concluded that TNF is dispensable for maximal
antileukemic response
[68]
. Thus, the roles of TNF/LTα3 are clearly depen-
dent on a variety of factors.
366
IL-2
IL-2 is a pleiotropic cytokine with critical effects on T-cell growth in general,
but it also acts to improve NK cell cytolytic activity, promote the genera-
tion of regulatory T cells, and contribute to activation-induced cell death
(AICD). It is produced primarily by CD4
+
T cells after their activation by spe-
cific MHC:antigen complexes and costimulatory molecules on APC. IL-2
itself regulates the expression of its own receptor (the IL-2R) and expression
of other related cytokine receptors (e.g., IL-7Rα, IL-4Rα)
[69,70]
.
IL-2 is one of the “common γ chain (γ
c
)” cytokines, that is, the γ chain of
the IL-2 receptor is also a component of the IL-4, IL-7, IL-9, IL-15, and
IL-21 receptors
[71]
. Interestingly, it is deficiency of this receptor chain that
results in X-linked severe combined immunodeficiency (SCID) in humans
[72]
, which demonstrates the critical importance of these cytokines in nor-
mal immune function. The IL-2 receptor itself comprises three different
chains and these combine to form low-, medium-, and high-affinity itera-
tions of the receptor. IL-2Rα, also known as CD25, is a low-affinity recep-
tor and is rapidly upregulated on activated (compared with nonactivated)
T cells. Dimeric IL-2Rβ and γ
c
complexes (IL-2Rβ/γ
c
) are expressed primarily
on memory T cells and NK cells, and this complex represents a moderate-
affinity receptor. The trimeric IL-2Rα/β/γ
c
is the high-affinity receptor and
is expressed on activated T cells, but also, importantly, on Tregs. It is thought
that this receptor is assembled after initial binding of IL-2 to IL-2Rα, fol-
lowed by the recruitment of IL-2Rβ and finally the addition of the γ
c
. Binding
of the intermediate- and high-affinity receptors leads to activation of three
major signaling pathways:
[1]
the phosphoinositol 3-kinase (PI3-K);
[2]
the
Ras-MAP kinase; and
[3]
the JAK/STAT pathway, and it is these signaling
pathways that mediate the broad effects of IL-2. Principally, JAK1 and JAK3,
as well as STAT5a/5b are utilized, but IL-2 is also known to utilize STAT1
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