Page 306 - Hematology_ Basic Principles and Practice ( PDFDrive )

254 Part III Immunologic Basis of Hematology

+
LCMV-specific CD8 T-cell response. This suggests that pDCs may
118
be required to enhance weak cytotoxic T-cell responses. A recent ACTIVATION OF OTHER ELEMENTS OF THE
study targeting Siglec-H by conditional genetic ablation specifically IMMUNE SYSTEM
induced specific pDC depletion and demonstrated a complex role
of pDCs. Siglec-H and pDCs depleted pDC-suppressed, antigen- DCs have proven to be quite versatile in their ability to interact with
+
specific CD4 T-cell responses in vivo, but they were required many constituents of the immune system. For example, they can acti-
+
to enhance the CD8 T-cell response to soluble and microbial vate NK T cells by presentation of the synthetic ligand α-galactosyl
antigens. 119 ceramide on CD1, inducing the production of cytokines such as
125
IFN-γ and resistance to tumors. CD1-restricted γδT cells, which
respond to microbial antigens from Mycobacterium tuberculosis and
B-CELL ACTIVATION other organisms, induce maturation of resting DCs and also induce
IL-12 production. This pathway and the IFN-γ secretion by activated
In addition to affecting T-cell function, DCs can also influence B-cell γδT cells provide the immune system with a source of activated
120
proliferation, isotype switching, and plasma cell differentiation. APCs, which can polarize Th1 responses. 126
DCs produce factors that activate and induce B-cell proliferation In summary, the influence of DCs on other cell types of the
121
(B-Lys and APRIL). Furthermore, DCs stimulate antibody immune system is broad and integrative (Fig. 23.3). Future studies
responses in a T-cell–independent manner against polysaccharide will ascertain the interplay between the myriad host cells and the
antigens. The initial interactions between B cells and DCs occur in innate and adaptive immune responses.
the T-cell area of lymph nodes and in the germinal centers of lymph
nodes or splenic red pulp (or both). Importantly, antigen-exposed
cDCs possess a specialized nondegradative pathway that allows them TOLERANCE AND AUTOIMMUNITY
to present internalized antigens in their native state for the engage-
ment of B-cell receptors on B cells. This is mediated by endocytosis DCs play a pivotal role in the balance between immunity and
of antigenic immune complexes through the inhibitory Fc receptor tolerance. DCs are important in the induction of both central and
FcγRIIB and recycling of the endocytic vesicle to the surface without peripheral tolerance. In the former, DCs play a role in deletion of
122
antigen degradation. The follicular DCs, which are present in autoreactive T cells in the thymus. In the latter, imDCs in their
germinal centers of lymph nodes and which constitute a different steady state induce T-cell deletion, anergy, or generation of Tregs,
class of DCs, participate in the maintenance of B-cell memory by which interfere with IL-2 production and proliferation of effector T
formation of multiple antigen–antibody complexes and continuous cells against self. 127
stimulation of B cells. The antigen–antibody complexes may remain In the thymus, medullary thymic epithelial cells (mTECs) are
in the lymph node for an extended period of time (up to months the major population responsible for inducing central tolerance.
or years). Autoreactive T cells in the thymus are negatively selected upon rec-
ognition of self-antigens, which are expressed at low levels by mTECs
via their expression of autoimmune regulator (AIRE) transcription
NATURAL KILLER CELL ACTIVATION factor. AIRE induces the release of stalled RNA polymerase II to
128
promote the ectopic expression of these self-antigens. Thymic DCs
The interactions between DCs and NK cells are complex and further contribute to negative selection in that they can cross-present the self-
underscore a role of DCs as a link between innate and adaptive antigens from mTECs to T cells in the thymus. DCs acquire antigen
8
immunity. Direct interactions between NK cells and mDCs can from apoptotic debris of mTECs, a consequence of normal turnover
129
result in NK-cell activation as well as the potentiation of their of the cells, or they can acquire intact antigens via antigen transfer
131
130
cytolytic activity, and, conversely, NK cells can induce further DC from mTECs, a process that may occur by tunneling nanotubes,
132
58
maturation. NK cells and DCs can form an immune synapse, prob- trogocytosis, or trafficking of mTEC-derived exosomes. In this
ably helping directional and confined secretion of cytokines as well as context, AIRE was also reported to control the transfer of antigen
133
facilitating receptor–ligand interactions with one another. Activated from mTECs to DCs. Additionally, circulating DCs from the
NK cells induce DCs through both cell contact (involving NKp30) periphery have also been shown to migrate to the thymus and play a
and TNF-α and IFN-γ secretion. In turn, activated DCs secrete role in negative selection by inducing clonal deletion of autoreactive
IL-12/IL-18, IL-15, and IFN-α/β, which enhance IFN-γ secretion, T cells or Treg development. 134
proliferation, and cytotoxicity of NK cells. In some conditions, NK In the periphery, how DCs induce tolerance is still an area of active
cells can lyse DCs through NKp30, although mDCs are protected investigation, although a number of possible mechanisms have been
from cytolysis. This might represent a form of “cellular editing” identified. These processes are critical because they limit harmful
whereby immature and tolerogenic DCs (tDCs) are cleared by NK immune responses to antigens that may not have been available
cells in the course of an ongoing immune response. 123 during thymic selection, or from autoreactive T cells that may have
135
It is thus possible that DC and NK cells play complementary escaped central tolerance. In the steady state, antigen delivery via
roles in sensing pathogens, such that DCs could be the first to the endocytosis receptor DEC-205 in imDCs was shown to induce
detect microbes through their expression of PRRs (TLRs, NOD T-cell tolerance, highlighting a function of DCs as promoters of naive
136
proteins), whereas NK may become activated in the absence of overt peripheral T-cell deletion. Using a genetic approach, Probst and
inflammation but in the presence of ligands for activating NK-cell colleagues showed that antigen expression in steady-state DCs also
+
receptors, such as in the setting of tumors (which frequently lose induced strong CD8 T-cell tolerance to immunodominant antigens
MHC class I expression or express NKG2D ligands, such as MHC and that this effect was dependent on negative costimulation via
class I polypeptide-related sequences A and B). In both situations, inhibitory receptors of the CD28 family, such as PD-1 and cytotoxic
either DCs or NK cells could create an inflammatory environment T lymphocyte–associated protein 4 (CTLA-4). 127,137
and induce the integrated activation of other cell types. Thus, in Production of indoleamine 2,3-dioxygenase (IDO) has been
138
mice, infection by murine cytomegalovirus (CMV) induces pDCs proposed to account for some of the tolerogenic potential of DCs.
+
to secrete high levels of IFN-α/β, but CD8α DCs are the major IDO is an enzyme that degrades the indole moiety of tryptophan and
producers of IL-12, and resistance to the virus is associated with other molecules and induces the production of immunoregulatory
+
expansion of Ly49H NK cells, driven by IL-12/IL-18. metabolites known as kynurenines. Local depletion of tryptophan
The interaction between NK cells and DCs is likely to take and increases in proapoptotic kynurenines affect T-cell proliferation
place early during the course of an immune response. This allows and survival. Induction of IDO in DCs has been postulated as one
138
DCs to exploit the ability of NK cells to kill tumor or virus- or means by which deletional tolerance occurs. DC-derived IDO can
parasite-infected cells and to cross-present this material to T cells. 124 promote T-cell tolerance by mechanisms that may or may not depend