Duration, combination and timing: the signal integration model of dendritic cell activation

doi:10.1016/j.it.2007.03.008

Trends in Immunology

Volume 28, Issue 5, May 2007, Pages 227-233

https://doi.org/10.1016/j.it.2007.03.008 Get rights and content

The activation of resting dendritic cells (DCs) is a crucial step in the initiation of adaptive immunity because it links peripheral events initiated by the encounter with pathogens to the activation and expansion of antigen-specific T lymphocytes in secondary lymphoid organs. It is well recognized that a wide variety of microbial products and endogenous signals can trigger DC activation, and that different DC subsets are specialized in inducing different classes of immune responses. In this review, we will focus on how different aspects of DC maturation are regulated not only by the nature of the DC maturation stimuli, but also by their duration, combination and timing, and provide an overview of how different modes of DC activation can affect T cell responses.

Section snippets

Stimuli that trigger DC maturation: a call for signal integration

Dendritic cells (DCs) are widely accepted as the most potent and versatile antigen-presenting cells (APCs) capable of inducing protective adaptive immune responses in addition to tolerance to self-antigens 1, 2, 3. In response to a variety of microbial and endogenous stimuli, resting DCs in peripheral tissues undergo a complex maturation process that might involve the regulation of thousands of genes that control distinct DC functions 4, 5, such as antigen capture and presentation, migration,

Duration of TLR stimulation

The importance of sustaining receptor stimulation in the immune system has been previously described in the context of T cell activation [22]. In T cells forming an immunological synapse with APCs, the signaling process is sustained by sequential engagements of TCRs, which are serially triggered by low affinity peptide–MHC complexes, and subsequently degraded. Removal of the APC or blocking of TCR engagement results in the immediate termination of the signaling process, detected as a sudden

Kinetic aspects of TLR stimulation and signaling

As discussed earlier, sustained TLR stimulation is required for the production of cytokine genes and is probably maintained by a serial receptor engagement process. This process requires that only a fraction of the receptors is initially triggered, leaving a substantial fraction free for subsequent engagement. In T cells, this is achieved by compartmentalization of TCR triggering at the immunological synapse. How this is achieved in the case of DCs and TLRs has yet to be established. It might

Combinatorial codes for control of polarizing cytokines

As mentioned previously, DCs can be exposed to a variety of stimuli both in peripheral tissues and, after migration, in secondary lymphoid organs. Several studies have documented how different stimuli can cooperate or synergize in the induction of particular aspects of DC maturation, primarily cytokine production. A striking example of this combinatorial regulation is provided by IL-12p70, a polarizing cytokine that promotes Th1 differentiation and mediates powerful systemic effects. DCs can

Time window for integration of stimulatory signals in DCs

Cytokine, in particular IL-12p70, production is regulated in DCs not only by the combination of stimuli but also by the order in which the stimuli are delivered over a defined period of time. IFNγ enhances IL-12p70 production only if given before TLR agonists, and the TLR synergy is more pronounced when TLR3 or TLR4 agonists are given before TLR8 agonists [43]. Finally, CD40 stimulation is maximally effective when given after a TLR stimulus [46]. Unsurprisingly, perhaps, this is the temporal

The signal integration model of DC activation

The data discussed in this review provide evidence for a possible signal integration model of DC activation. Based on this model, the T cell stimulatory potential of DCs depends on the duration and combination of stimulatory signals and is progressively acquired as the time of exposure increases (Figure 3). Therefore, DC activation is not an intrinsic program that is put in motion by an inciting stimulus but, instead, can be viewed as a complex nonlinear dynamic system that continuously adjusts

Concluding remarks

We have discussed how individual DCs could integrate different signals in peripheral organs and then migrate to the draining lymph node, where they induce different types of T cell responses. However, it has been shown that migratory DCs can transfer antigen to lymph node-resident DCs that then exert the effector function (e.g. IL-12 production and CD8⁺ T cell priming) [71]. It would be important to understand whether the microbial information received by DCs in the periphery is also

Acknowledgements

The work on dendritic cells in our laboratories is supported by grants from the European Community (DC-THERA, grant number LSHB-CT-2004–512074, and MUVAPRED, grant number LSHP-CT-2003–503240) and the Swiss National Science Foundation (grant number 3100AO-112678). The Institute for Research in Biomedicine is supported by the Helmut Horten Foundation.

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Trends in Immunology

ReviewDuration, combination and timing: the signal integration model of dendritic cell activation

Section snippets

Stimuli that trigger DC maturation: a call for signal integration

Duration of TLR stimulation

Kinetic aspects of TLR stimulation and signaling

Combinatorial codes for control of polarizing cytokines

Time window for integration of stimulatory signals in DCs

The signal integration model of DC activation

Concluding remarks

Acknowledgements

Blood

Trends Immunol.

Trends Immunol.

Immunity

Immunol. Today

Blood

Trends Immunol.

J. Biol. Chem.

Trends Immunol.

J. Biol. Chem.

Blood

Blood

Blood

Immunity

Mol. Cell

Immunity

Immunity

Immunity

Cell

Immunity

Immunity

Immunol. Today

Tolerogenic dendritic cells

Annu. Rev. Immunol.

Dendritic-cell control of pathogen-driven T-cell polarization

Nat. Rev. Immunol.

Dendritic cells in a mature age

Nat. Rev. Immunol.

Transcriptional reprogramming of dendritic cells by differentiation stimuli

Eur. J. Immunol.

Subsets of human dendritic cell precursors express different Toll-like receptors and respond to different microbial antigens

J. Exp. Med.

Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells

Eur. J. Immunol.

Toll-like receptor signaling

Nat. Rev. Immunol.

New insights into the regulation of TLR signaling

J. Leukoc. Biol.

Myeloid C-type lectins in innate immunity

Nat. Immunol.

Toll-like receptor control of the adaptive immune responses

Nat. Immunol.

Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T–T help via APC activation

J. Exp. Med.

Help for cytotoxic-T-cell responses is mediated by CD40 signalling

Nature

T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions

Nature

Immunology. Licence to kill

Nature

The natural killer T (NKT) cell ligand α-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells

J. Exp. Med.

Review
Duration, combination and timing: the signal integration model of dendritic cell activation