Responding To Danger

The default response of the inductive sites of the mucosal immune system is decidedly anti-inflammatory, if not tolerogenic. The default response elicited by dendritic cells entering the lymph nodes and spleen from the effector sites of mucosal immune system is actively tolerogenic. However, several different kinds of signal induce immature dendritic cells to mature with phenotypes that elicit effector responses. While infection of dendritic cells by certain pathogens can downregulate expression of IL-12 (156) or induce production of IL-10 (157,158), most pathogens upregulate IL-12 production (159). LPS can induce dendritic cells to mature with either the so-called DC1 or DC2 phenotypes, which generate Th1 or Th2 effector cells. LPS stimulation of bone marrow-derived dendritic cells activates cyclooxygenase-2, and the resulting PGE2 stimulates production of IL-10 (160), which supports generation of TH2 effector cells. LPS stimulation of peripheral blood dendritic cells upregulates expression of MHC Class II, B7-1, B7-2, and CD40, and it also stimulates expression of TNF-a, IL-6, IL-8, IL-12 (161), leading to efficient generation of TH1 effector cells. Stimulation of long-term cultures of spleen-derived dendritic cells with TNF-a and IL-1^ induces them to express MHC Class II, B7-2, CD40, and IL-12 (162). Bone marrow cells are activated by necrotic cells, but not by apoptotic cells (163). This may be because necrotic cells release Hsp 70, which stimulates dendritic cell antigen uptake and maturation (164). Interestingly, dendritic cell maturation also is activated by mechanical stress (163) (Fig. 2).

Once a cellular immune response has been initiated, CD40L on effector T lymphocyte also may activate CD40 on immature DCs to stimulate their activation (165,166). DCs that are activated by infection, an inflammatory signaling milieu, or CD40 stimulation are likely to be loaded with autoantigens as well as with foreign antigens. Autoantigen-specific TRN regulatory cells as well as the regulatory T cells that have been generated under previous, non-inflamed conditions, tend to prevent DC1 and DC2 DCs loaded with autoantigens from activating naive autoantigen-specific T cells. However, CD40 signaling in the presence of TNF-a overcomes the tolerogenic influence of IL-10 (165). TrN cells, which secrete IL-10, lose their capacity to function as regulatory cells in the presence of high concentrations of IL-2. TH3 regulatory cells appear more robust.

Figure 2 (See color insert.) Lymphocyte and dendritic cell (DC) cycles in the ocular surface system. Naïve B cells are activated in the mucosa-associated lymphoid tissues (CALT, GALT, etc.) under the influence of antigens presented by mature dendritic cells (DCs) and activated B cells (not shown). They enter the lymphatics as IgA+ plasmablasts, then migrate to the lacrimal glands, where they mature as IgA+ plasma cells. Immature DCs enter the lacrimal glands, become loaded with lacrimal autoantigens, and, under the influence of the local milieu, mature to either an effector-activating or a tolerogenic phenotype. Mature DCs migrate from the lacrimal gland (and conjunctival space) to the lymph nodes, where, depending on their phenotype, they activate naïve T cells to mature with memory, effector, or regulatory phenotypes.

Figure 2 (See color insert.) Lymphocyte and dendritic cell (DC) cycles in the ocular surface system. Naïve B cells are activated in the mucosa-associated lymphoid tissues (CALT, GALT, etc.) under the influence of antigens presented by mature dendritic cells (DCs) and activated B cells (not shown). They enter the lymphatics as IgA+ plasmablasts, then migrate to the lacrimal glands, where they mature as IgA+ plasma cells. Immature DCs enter the lacrimal glands, become loaded with lacrimal autoantigens, and, under the influence of the local milieu, mature to either an effector-activating or a tolerogenic phenotype. Mature DCs migrate from the lacrimal gland (and conjunctival space) to the lymph nodes, where, depending on their phenotype, they activate naïve T cells to mature with memory, effector, or regulatory phenotypes.

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