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CHAPTER 21 to evolutionarily conserved molecules found in microbes, parasites
and viruses. Pattern recognition receptors include toll-like receptors
4,5
DENDRITIC CELLS AND (TLRs), nucleotide-binding oligomerization domain-like receptors,
retinoic acid-inducible gene 1-like receptors, and numerous C-type
ADAPTIVE IMMUNITY lectins. Pattern recognition receptors recognize a wide array of ligands,
such as single- or double-stranded RNA, lipopolysaccharides, and other
microbial constituents. DCs express pattern recognition receptors and
respond to pattern recognition receptor agonists by becoming potent
Madhav Dhodapkar, Crystal L. Mackall, and Ralph M. Steinman* immunostimulatory cells and by presenting captured antigens to T cells
in the context of major histocompatibility antigens. Pattern recogni-
tion receptors on DCs can also be activated via noninfectious stimuli
induced by tissue damage and malignant cells, including uric acid crys-
SUMMARY tals and heat shock and chromatin proteins. Such pathways are likely
important for activating DCs toward tumor-associated antigens follow-
Dendritic cells are a multifunctional group of cells that serve as sentinels of ing transplantation or in disease states such as cancer or allergy.
the immune system and thus regulate many immune functions. Dendritic Activated or matured DCs can prime resting NK cells, which then
cells play a central role in initiating adaptive immune responses to patho- reciprocally act back on DCs, enhancing DC maturation and initiat-
6
gens and initiating antitumor immune responses. Dendritic cell receptors ing adaptive immune responses. NK cells can also negatively regulate
sense environmental stimuli and can respond rapidly to both foreign patho- DC function by killing immature DCs, a feature that is important in
gens and danger signals derived from tissue damage or immune complexes. NK mediated graft-versus-leukemia (GVL), without graft-versus-host
7
Through their capacity to present antigen to T cells in immune-activating or disease (GVHD), following hematopoietic stem cell transplantation.
immune-dampening contexts, dendritic cells can both induce T-cell prolifer- Such immune crosstalk between NK cells and DCs, is emblematic of the
8–10
exquisite interdependence and complexity of the immune response.
ation (activation) or lack of activation (tolerance). In this way, dendritic cells
help regulate immune responses mediated by T cells and B cells of the adaptive
immune system. This chapter describes the varied types and functions of this DENDRITIC CELLS AND ADAPTIVE IMMUNITY
important class of cells.
Adaptive immunity imparts immune memory to the host, which allows
a more rapid and more effective immune response to rechallenge with
the same antigen. Adaptive immunity is mediated by B and T lympho-
cytes, but its induction is largely regulated by DCs. Immune memory
FUNCTIONS OF DENDRITIC CELLS increases the frequency and function of antigen-specific lymphocytes,
leading to enhanced levels of protective antibodies, cytokines, and killer
Host defense is mediated by innate and adaptive immune responses,
and dendritic cells (DCs) play essential roles in linking together innate molecules. Through an elaborate series of gene rearrangements, hyper-
and adaptive immunity. The innate immune response provides rapid mutation, and selection, antibody on B cells and T-cell receptors on
1–3
resistance to pathogens, but the potency of innate responses does not T cells provide remarkable diversity and specificity. This array might
increase following initial exposure. Adaptive responses, mediated by be thought of as the largest combinatorial library of specificities in the
B and T lymphocytes, generate immune memory, resulting in more world! 1,3,11
rapid and more potent responses following antigen reexposure (Chaps. DCs function as sentinels of the immune system (Table 21–1)
75 and 76). and provide a critical bridge between innate and adaptive immunity.
Indeed, the presence of antigen and lymphocyte is rarely sufficient to
induce adaptive immune responses. Rather, a third party, the DC system
DENDRITIC CELLS AND INNATE IMMUNITY of antigen-presenting cells provides the pivotal immune initiation sig-
DCs provide innate immune resistance through production of cytok- nal required to induce an adaptive immune response. DCs sense a wide
ines, including interleukin (IL)-12 and type I interferons, and by acti- range of environmental stimuli, producing cytokines, such as IL-12 and
vating other innate lymphocytes such as natural killer (NK) cells, NKT type I interferons that help stimulate immune responses. DCs express
cells, and γδ T cells (Chap. 75). Innate responses are most often ini- most types of TLRs, with specific subsets of DCs differentially express-
tiated by “pattern recognition receptors” (Chap. 20), which respond ing distinct TLRs; for example, plasmacytoid DCs express significant
12
levels of TLR-7 and TLR-9. DCs can also respond to endogenous stim-
uli, ranging from inflammatory cytokines, including tumor necrosis
factor (TNF)-α, IL-1, or interferons, to byproducts of cell death or tissue
damage. DCs capture microbes and tumor cells, processing their com-
ponent antigens for presentation to the adaptive immune system. DC
Acronyms and Abbreviations: CD, cluster of differentiation; CMV, cytomegalo-
virus; DC, dendritic cell; GM-CSF, granulocyte-monocyte colony-stimulating factor; activation, via innate immune receptors, leads to DC maturation and
GVHD, graft-versus-host disease; GVL, graft-versus-leukemia; Ig, immunoglobulin; initiation of adaptive immunity. In addition to antigen processing and
IL, interleukin; M-CSF, monocyte colony-stimulating factor; MHC, major histocom- presentation, sentinel DCs produce chemokines and cytokines. They
patibility complex; NK, natural killer; Th, T helper; TLR, toll-like receptor; TNF, tumor migrate to lymphoid tissues, where they recruit naïve antigen-specific
necrosis factor; Tr, T regulatory. lymphocytes and instruct their subsequent development.
A variety of DC subsets exist and the biology of DC activation can
vary significantly according to the exposure. During immunization,
DCs initiate clonal expansion of T cells and can directly and indirectly
* Deceased. Substantial portions of his contribution have been retained in the influence the growth of B cells. In addition, DCs can modulate differen-
current version of this chapter. tiation of lymphocytes, such that the properties of the lymphocytes are

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