Martien L. Kapsenberg

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

Dendritic cells (DCs) are central in the orchestration of the various forms of immunity and tolerance. Their immunoregulatory role mainly relies on the ligation of specific receptors that initiate and modulate DC maturation resulting in the development of functionally different effector DC subsets that selectively promote T helper 1 (TH1)-, TH2- or regulatory T-cell responses. These DC-priming receptors include pattern recognition receptors (PRRs), which discriminate between (groups of) pathogens, as well as receptors that bind tissue factors that are produced either constitutively or in response to infection with pathogens, and characterize the type of tissue and the pathogen-specific response pattern of this tissue. Although it is becoming increasingly clear that the selective development of T-cell-polarizing DC subsets is related to the ligation of particular receptors that are involved in DC maturation, several inconsistencies with this concept remain.

Development of Th1-Inducing Capacity in Myeloid Dendritic Cells Requires Environmental Instruction

Dendritic cells (DC) are key initiators of primary immune responses. Myeloid DC can secrete IL-12, a potent Th1-driving factor, and are often viewed as Th1-promoting APC. Here we show that neither a Th1- nor a Th2-inducing function is an intrinsic attribute of human myeloid DC, but both depend on environmental instruction. Uncommitted immature DC require exposure to IFN-γ, at the moment of induction of their maturation or shortly thereafter, to develop the capacity to produce high levels of IL-12p70 upon subsequent contact with naive Th cells. This effect is specific for IFN-γ and is not shared by other IL-12-inducing factors. Type 1-polarized effector DC, matured in the presence of IFN-γ, induce Th1 responses, in contrast to type 2-polarized DC matured in the presence of PGE2 that induce Th2 responses. Type 1-polarized effector DC are resistant to further modulation, which may facilitate their potential use in immunotherapy.

Microbial Compounds Selectively Induce Th1 Cell-Promoting or Th2 Cell-Promoting Dendritic Cells In Vitro with Diverse Th Cell-Polarizing Signals

Upon microbial infection, specific Th1 or Th2 responses develop depending on the type of microbe. Here, we demonstrate that different microbial compounds polarize the maturation of human myeloid dendritic cells (DCs) into stably committed Th1 cell-promoting (DC1) or Th2 cell-promoting (DC2) effector DCs that polarize Th cells via different mechanisms. Protein extract derived from the helminth Schistosoma mansoni induced the development of DC2s that promote the development of Th2 cells via the enhanced expression of OX40 ligand. Likewise, toxin from the extracellular bacterium Vibrio cholerae induced development of DC2s as well, however, via an OX40 ligand-independent, still unknown mechanism. In contrast, toxin from the intracellular bacterium Bordetella pertussis induced the development of DC1s with enhanced IL-12 production, which promotes a Th1 cell development. Poly(I:C) (dsRNA, mimic for virus) induced the development of extremely potent Th1-inducing DC1, surprisingly, without an enhanced IL-12 production. The obtained DC1s and DC2s are genuine effector cells that stably express Th cell-polarizing factors and are unresponsive to further modulation. The data suggest that the molecular basis of Th1/Th2 polarization via DCs is unexpectedly diverse and is adapted to the nature of the microbial compounds.

Alpha-type-1 polarized dendritic cells: A novel immunization tool with optimized CTL-inducing activity

Using the principle of functional polarization of dendritic cells (DCs), we have developed a novel protocol to generate human DCs combining the three features critical for the induction of type-1 immunity: (a) fully mature status; (b) responsiveness to secondary lymphoid organ chemokines; and (c) high interleukin-12p70 (IL-12p70)-producing ability. We show that IFN-α and polyinosinic:polycytidylic acid (p-I:C) synergize with the “classical” type-1-polarizing cytokine cocktail [tumor necrosis factor α (TNFα)/IL-1β/IFNγ], allowing for serum-free generation of fully mature type-1-polarized DCs (DC1). Such “α-type-1-polarized DC(s)” (αDC1) show high migratory responses to the CCR7 ligand, 6C-kine but produce much higher levels of IL-12p70 as compared to TNFα/IL-1β/IL-6/prostaglandin E2 (PGE2)-matured DCs (sDC), the current “gold standard” in DC-based cancer vaccination. A single round of in vitro sensitization with αDC1 (versus sDCs) induces up to 40-fold higher numbers of long-lived CTLs against melanoma-associated antigens: MART-1, gp100, and tyrosinase. Serum-free generation of αDC1 allows, for the first time, the clinical application of DCs that combine the key three features important for their efficacy as anticancer vaccines.

The skin immune system: progress in cutaneous biology

The skin is an active, and in many ways unique, immunological microenvironment quite different from the other primary interfaces between the body and the environment (namely the mucosae). Here Jan D. Bos and Martien L. Kapsenberg identify the components of the skin immune system and describe the inflammatory and immunological responses that they can mount. New findings with regard to the immunophysiology and physiopathology of the human integument are emphasized.

Dendritic cell-mediated T cell polarization

Effective defense against diverse types of micro-organisms that invade our body requires specialized classes of antigen-specific immune responses initiated and maintained by distinct subsets of effector CD4+ T helper (Th) cells. Excessive or detrimental (e.g., autoimmune) responses by effector T cells are controlled by regulatory T cells. The optimal balance in the development of the different types of effector and regulatory Th cells is orchestrated by dendritic cells (DC). This review discusses the way DC adapt the T cell response to the type of pathogen, focusing on the tools that DC use in this management of the T cell response.

Helicobacter pylori modulates the T helper cell 1/T helper cell 2 balance through phase-variable interaction between lipopolysaccharide and DC-SIGN

The human gastric pathogen Helicobacter pylori spontaneously switches lipopolysaccharide (LPS) Lewis (Le) antigens on and off (phase-variable expression), but the biological significance of this is unclear. Here, we report that Le+ H. pylori variants are able to bind to the C-type lectin DC-SIGN and present on gastric dendritic cells (DCs), and demonstrate that this interaction blocks T helper cell (Th)1 development. In contrast, Le− variants escape binding to DCs and induce a strong Th1 cell response. In addition, in gastric biopsies challenged ex vivo with Le+ variants that bind DC-SIGN, interleukin 6 production is decreased, indicative of increased immune suppression. Our data indicate a role for LPS phase variation and Le antigen expression by H. pylori in suppressing immune responses through DC-SIGN.

Functional subsets of allergen-reactive human CD4+ T cells

After a period of resistance, the concept of human helper T (TH)-cell subsets is gaining currency. This is the result of analyses from a number of laboratories on the cytokine profiles of T-cell clones prepared from chronically-infected and hypersensitive individuals. Here, Martien Kapsenberg and colleagues summarize these studies and speculate on the significance of skewed TH1 and TH2 responses.

Predominance of «memory» T cells (CD4+, CDw29+) over «naive» T cells (CD4+, CD45R+) in both normal and diseased human skin

SummaryAbsolute numbers of CD3+ T lymphocytes and their subpopulations were determined and statistically evaluated in the lesional skin of psoriasis, atopic dermatitis, nummular dermatitis, pityriasis rosea, and lichen planus. Skin sections were divided into horizontal layers and the numbers of CD3+ T cells as well as CD4+ inducer and CD8+ suppressor-cytotoxic T-cell subsets were counted. In addition, absolute numbers of the two subpopulations of inducer T cells, i.e., “memory” (4B4+ 2H4-) and “naive” (4B4- 2H4+) were evaluated. Unexpectedly, epidermal infiltration by T cells was highest in psoriasis and lowest in atopic dermatitis. In most cases, this exocytosis was dominated by CD8+ suppressor/cytotoxic T lymphocytes, with a minimal epidermal mean CD4/mean CD8 ratio of 0.04 in pityriasis rosea and a maximum of 0.48 in psoriasis. Inducer T cells within the epidermis were almost exclusively of the 4B4+ 2H4- “memory” T-cell subpopulation, whereas 4B4- 2H4+ “naive” T cells were extremely uncommon in lesional epidermis. Similar results were obtained for dermal T cells in all diseases studied, i.e., 4B4- 2H4+ “naive” T cells were relatively rare. Papillary dermis infiltration by T cells was highest in lichen planus where a mean CD4/mean CD8 ratio of 1.10, the minimum in this comparative study, was obtained. The mean CD4/mean CD8 ratio of the papillary infiltrate was highest in atopic dermatitis (4.12). Our results indicate disease-specific and significantly different infiltration patterns of T-lymphocyte subsets in the chronic inflammatory dermatoses investigated. The predominant presence of the CD4+ 2H4- “memory” subpopulation of CD4+ T cells in all diseases studied as well as in normal human skin (reported previously) seems to indicate that the skin immune system is rather unidirectional in its increase in this subpopulation of the inducer T-cell subset. This predominance of the “memory” subpopulation thus indicates that most T cells of normal and diseased human skin are already primed, i.e., have already met their specific ligand in a MHC II context.

IL-4 Is a Mediator of IL-12p70 Induction by Human Th2 Cells: Reversal of Polarized Th2 Phenotype by Dendritic Cells

IL-12 is a key inducer of Th1-associated inflammatory responses, protective against intracellular infections and cancer, but also involved in autoimmune tissue destruction. We report that human Th2 cells interacting with monocyte-derived dendritic cells (DC) effectively induce bioactive IL-12p70 and revert to Th0/Th1 phenotype. In contrast, the interaction with B cells preserves polarized Th2 phenotype. The induction of IL-12p70 in Th2 cell-DC cocultures is prevented by IL-4-neutralizing mAb, indicating that IL-4 acts as a Th2 cell-specific cofactor of IL-12p70 induction. Like IFN-γ, IL-4 strongly enhances the production of bioactive IL-12p70 heterodimer in CD40 ligand-stimulated DC and macrophages and synergizes with IFN-γ at low concentrations of both cytokines. However, in contrast to IFN-γ, IL-4 inhibits the CD40 ligand-induced production of inactive IL-12p40 and the production of either form of IL-12 induced by LPS, which may explain the view of IL-4 as an IL-12 inhibitor. The presently described ability of IL-4 to act as a cofactor of Th cell-mediated IL-12p70 induction may allow Th2 cells to support cell-mediated immunity in chronic inflammatory states, including cancer, autoimmunity, and atopic dermatitis.