Biomedical Engineering Reference
In-Depth Information
As a signal converter, Fn14
TRAIL replaces a
proinflammatory signal with one that knocks out
bystander activated T cells.
In bridging the TWEAK:Fn14 and TRAIL:TRAIL-R
pathways, this chimeric protein interferes with both
innate and adaptive immunity.
Fn14
cellular congregation is mitigated, as each cell carries its
own triggers in immediate proximity to their cognate recep-
tors. CLBP can thus be viewed as fusion proteins that serve
to anchor ligands in proximity to their receptors and thereby
foster cis auto-signaling, and in effect, community indepen-
dence. There was a compelling logic to turn to FasL
(CD95L, CD178) in the design of a paradigmatic CLBP.
Within hours after their antigen receptors are engaged,
T cells upregulate their expression of Fas (CD95) receptors,
which acquire apoptosis-inducing functionality upon pro-
longed cell activation [82]. Importantly, antigen receptor
engagement is also accompanied by transient neoexpression
of FasL on activated T cells [83]. Thus, with concurrent
expression of Fas and FasL by the same and other activated
T cells during an immune response [84-86], a T cell might
have only 3 or 4 days to perform its effector function before
being targeted for destruction by suicide or fratrici-
de/sororicide [85,87-89]. The appreciation of surface
FasL as both an autocrine- and paracrine-acting agent
instantly made it an interesting candidate for CLBP design.
Our first paradigmatic CLBP, CD40
TRAIL tethers TRAIL to the cell surface, with
surface-associated TRAIL known to be more func-
tional than soluble TRAIL [81].
TRAIL, by virtue of the highly pleiotropic
functions attributed to its component parts, has the potential
to mediate a complex array of activities, which collectively
provide a beneficial effect in the setting of autoimmunity.
This was
Thus Fn14
corroborated with our demonstration that
Fn14
TRAIL prevents auto-antigen-induced EAE in mice,
with an efficacy that is substantially greater than that for
either of its component parts (as Fn14
Ig and soluble TRAIL
derivatives) when used in isolation or in combination [80].
This study further suggested that Fn14
TRAIL can reverse
the enhanced permeability of the blood-brain barrier in
diseased animals, providing yet another explanation for
the high therapeutic efficacy of this fusion protein in the
EAE model.
FasL, was geared
toward promoting autoinhibition of activated effector T cells
[90]. The CD40 component binds to CD40L (CD154) neo-
expressed on activated T cells, while the FasL component
triggers the pro-apoptotic Fas receptor on these cells. The
logic for pairing these particular proteins was several - fold:
30.5 FROM TRANS TO CIS SIGNAL
CONVERSION: DRIVING AUTO-SIGNALING
Selective targeting of activated T cells is made possible
by choosing CLBP components that engage surface
counter-receptors (CD40L and Fas) that are neoex-
pressed, and acquire full
For TSCP and TSRP, the receptor for the converted signal
resides on second- and third-party cells, respectively. But
what if the receptor for the converted signal is co-localized
on the same cell that bears the surface signaling ligand that is
being converted? This kernel of a thought seeded another
category of SCP, designed to redirect converted signals back
to the same cell. Such cis loop-back proteins (CLBP)
generate auto-signaling loops, and by judiciously choosing
the components of a given CLBP, one can take advantage of
forward- and reverse-signaling features of the fusion
protein's surface molecular targets to reinforce the efficacy
of the converted signal. In this way, CLBP can be configured
to double as both signal converting and dual co-signaling
agents.
The concept of autocrine signaling has traditionally been
framed in terms of a cell secreting signal molecules that can
bind its own surface receptors. This type of signaling is
presumably most effective when it occurs in the vicinity of
neighboring cells of the same type since under these cir-
cumstances there are higher local concentration of the
secreted signal. This engenders a community effect that
encourages groups of identical cells to make the same
developmental decisions and respond coordinately as a
group. However, in the special case where autocrine signal-
ing is driven by surface-associated ligands, the demand for
functionality,
following
T-cell activation [82].
CD40
FasL can convert the outbound immune-activat-
ing signal emanating from CD40L into a pro-apoptotic
FasL signal redirected back to the same cell.
The two signaling pathways are functionally con-
nected, in that reverse signaling through CD40L
sensitizes activated T cells to Fas-mediated apoptosis
[91]. Thus, CD40
FasL can function as a dual-triggering
agent, by generating a CD40L reverse signal that
potentiates the Fas-mediated pro-apoptotic signal and
renders the cells more susceptible to activation-induced
apoptosis.
CD40
FasL tethers FasL to cell surfaces, thereby
invoking surface-associated FasL's higher efficacy,
as compared to soluble FasL [41,42].
This collection of mechanistic features exemplify the
kind of elegant design that is possible when selecting SCP
components, as one draws upon interlacing and reinforcing
functionalities in the pairing process.
The functionality of CD40
FasL was documented exper-
imentally, with strong evidence that a cis autoinhibitory
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