Biology Reference
In-Depth Information
The immune system certainly did not evolve to mediate alloimmunity.
Rather, anti-pathogen fitness, tempered by the need to avoid autoimmu-
nity, was probably the major driving force. We therefore begin with a brief
comparison of antigen presentation during pathogen responses to that
during GVHD, to highlight some major differences, which will frame the
discussion of APCs in GVHD.
A working and simplified paradigm for APC function in infection holds that
DCs are primary stimulators of pathogen-reactive naïve T cells
[5,6]
. DCs
encompass many different types of cells with distinct ontogeny and func-
tions
[7-9]
, which have in common the expression of CD11c and the ability to
stimulate T cells. The notion of the importance of DCs is supported by many
studies wherein adaptive T-cell responses were found to be diminished in
mice wherein CD11c
+
cells are inducibly or constitutively depleted
[10-19]
.
DCs have been proposed to exist in “immature” and “mature” states, though
no doubt this is again an oversimplification. “Immature” DCs have been
proposed to reside in both secondary lymphoid tissues (SLTs) and periph-
eral tissues, particularly barrier organs such as skin and bowel. They are
specialized for uptake of pathogen-derived antigens via endocytosis, pino-
cytosis, and an array of surface receptors such as C-type lectins
[20-22]
. DCs
are also equipped with multiple classes of pathogen-associated molecular
pattern receptors (PAMPRs), distributed in the various subcellular compart-
ments where invading pathogens are found, which deliver signals that mold
the “maturation” or activation process and consequently the ability of DCs
(and other APCs) to prime T cells
[23-25]
. DCs also receive reciprocal signals
from the T cells they activate (for example CD40L and cytokines). During
the maturation process, the expression of major histocompatibility complex
(MHC):peptide complexes is upregulated and stabilized on the cell surface
[26,27]
. In concert, DCs increase expression of costimulatory molecules and
cytokines that shape the adaptive immune response. Tissue DCs can migrate
to draining lymph nodes where they can either directly interact with T cells
or serve as a source of pathogen-derived antigens for SLT-resident APCs
[28]
.
DCs that are already resident in SLT can be directly infected and can acquire
antigen transported via the lymphatic system. An antigen-bearing DC in
SLT is well positioned to sample large numbers of T cells and activate rare
T cells with T-cell receptors (TCRs) specific for pathogen-derived peptides.
A key feature of this model for adaptive immunity is that APC maturation is
relatively restricted to cells presenting foreign antigens. Indeed, regulation
of DC maturation via pathogen-derived signals has been hypothesized as a
key mechanism whereby the immune system distinguishes self from non-
self
[29]
. These DCs are also the targets of the immune response, and thus
activated APCs are eliminated as the infection is controlled, which can, in
turn, downregulate pathogen-induced T-cell responses. Of course, DCs par-
ticipating in infectious responses also present self-antigen, the same type of
antigen that is targeted in GVHD responses. Yet, clinically significant auto-
immunity is rare.
174
Much of the prior discussion on DCs can be applied to the other major
classes of hematopoietic APCs. Each can be activated by PAMPs, can
variably indirectly present exogenous antigens, and can activate T cells,
including naïve T cells. These varied APCs differ in their tissue distribution,
their location within a given tissue, and their location in SLTs. How and why
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