T-cell priming by type-1and type-2 polarized dendritic cells: the concept of a third signal

doi:10.1016/S0167-5699(99)01547-9

Immunology Today

Volume 20, Issue 12, 1 December 1999, Pages 561-567

Immunology Today

https://doi.org/10.1016/S0167-5699(99)01547-9 Get rights and content

Abstract

Primary immune responses are initiated by dendritic cells (DCs), which inform naive T helper (Th) cells about invading pathogens, providing an antigen-specific ‘signal 1’ and a costimulatory ‘signal 2’. Considering recent findings that myeloid DCs developing and maturing in different conditions are functionally different, Pawel Kaliński and colleagues suggest that migrating DCs carry an additional ‘signal 3’, contributing to the initial commitment of naive Th cells into Th1 or Th2 subsets.

Section snippets

DCs as carriers of pathogen-related information

DCs are believed to provide the lymph-node-based naive Th cells with two pathogen-related signals: the information about its antigenic structure and its pathogenicity. Immature DCs, residing in peripheral tissues, can be activated by the pathogen either directly, or indirectly, via the pathogen-induced nonspecific tissue response. Activated DCs transiently increase the intensity of their Ag uptake and terminate this process after several hours. This confers a relative selectivity of Ag uptake,

APC-related factors affect the cytokine profiles of Th cells

The control of the development of naive Th cells into Th1 or Th2 subsets by pathogen-, T-cell-, and antigen-presenting cell (APC)-derived factors, as well as by stromal factors, has been reviewed extensively1, 6, 7, 8. IL-4, originating from CD4⁺ T cells and possibly also other sources such as mast cells, is the best-known example of an APC-independent factor with a potent impact on the cytokine profile of Th cells6, 7.

An impressively large proportion of the known Th1/Th2-polarizing mechanisms

Different types of APC and the cytokine production of responding Th cells

In accordance with the potent polarizing activity of IL-12, Ag-presentation by APCs with different abilities to produce IL-12, for instance, B cells compared with monocytes, macrophages or DCs, results in different patterns of cytokine production in responding T cells18, 19, 20. An interesting possibility is that the type of Th-cell responses can also be differentially influenced by DCs of different lineages, such as lymphoid and myeloid DCs. Whereas lymphoid DCs are mainly considered to

Direct modulation of IL-12 production by pathogens

Until recently, myeloid DCs were often regarded as a Th1-driving APC type, as judged by their ability to produce IL-12. However, several in vitro and in vivo studies show that DCs are good inducers of both Th1 and Th2 cytokines in naive Th cells19, 27, 28, 29. An essential discriminative factor appears not to be the ability to produce IL-12 per se, but rather the level of IL-12 produced27, 30.

The amounts of IL-12 produced can be up- or downmodulated by pathogens. Many intracellular pathogens

Modulation of APC activity by healthy and diseased tissues

The anterior chamber of the eye is probably the best-studied example of an APC-modulating environment. APCs within the ciliary body of the eye have a distinct delayed-type hypersensitivity (DTH)-suppressive function⁴⁰, mediated by the induction of regulatory T cells⁴¹. The suppression of DTH is parallelled by undisturbed, or even enhanced, antibody production (indicative of a shift from Th1-type to Th2-type⁴² or Th3-type responses), dominated by the production of transforming growth factor β

In vitro-maturing DCs: polarization by inflammatory mediators

Among the possible mechanisms of tissue-dependent modulation of the Th1- and Th2-promoting capacity of myeloid DCs, an interesting option is the modulation of their IL-12-producing capacity by inflammatory mediators at different stages of DC development (Fig. 1). An insight into this mechanism can be obtained in an in vitro model of monocyte-derived DCs (Ref. 62).

PGE₂ is a common inflammatory product of stromal fibroblasts and epithelia⁶³, and might serve as an example of one type of modulatory

Implications: lessons from someone else’s experience?

The above observations suggest a scenario in which migrating DCs provide lymph-node-based naive Th cells with three signals: ‘signal 1’, giving information about the identity of the invader; ‘signal 2’, giving information about the Ag-related pathogenic potential; and ‘signal 3’, mediating the DC-dependent component of the early polarization of primary Th-cell responses (Fig. 2). This third signal, resulting from the character of a pathogen-induced, nonspecific tissue response, reflects both

Acknowledgements

We thank T.R. Mossman, K. Shortman, M. Moser and F. Koning for their critical comments and stimulating discussion, and J.H.N. Schuitemaker for the design of the figures.

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ViewpointT-cell priming by type-1and type-2 polarized dendritic cells: the concept of a third signal

Abstract

Section snippets

DCs as carriers of pathogen-related information

APC-related factors affect the cytokine profiles of Th cells

Different types of APC and the cytokine production of responding Th cells

Direct modulation of IL-12 production by pathogens

Modulation of APC activity by healthy and diseased tissues

In vitro-maturing DCs: polarization by inflammatory mediators

Implications: lessons from someone else’s experience?

Acknowledgements

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Viewpoint
T-cell priming by type-1and type-2 polarized dendritic cells: the concept of a third signal