Dendritic cells: arbiters of immunity and immunological tolerance

Abstract

Dendritic cells (DCs) link innate immune sensing of the environment to the initiation of adaptive immune responses. Given their supreme capacity to interact with and present antigen to T cells, DCs have been proposed as key mediators of immunological tolerance in the steady state. However, recent evidence suggests that the role of DCs in central and peripheral T-cell tolerance is neither obligate nor dominant. Instead, DCs appear to regulate multiple aspects of T-cell physiology including tonic antigen receptor signaling, priming of effector T-cell response, and the maintenance of regulatory T cells. These diverse contributions of DCs may reflect the significant heterogeneity and "division of labor" observed between and within distinct DC subsets. The emerging complex role of different DC subsets should form the conceptual basis of DC-based therapeutic approaches toward induction of tolerance or immunization.

Figure 1.

Dendritic cell development and subsets. Shown are functionally and genetically distinct DC subsets identified in the mouse spleen and intestinal lamina propria (LP), their major developmental regulators, and key surface markers. The known counterparts of these subsets in the human peripheral blood are also indicated.

Figure 2.

The proposed “division of labor” within dendritic cell subsets. In a traditional view of DC function (A), a single DC detects pathogen, secretes inflammatory cytokines, and migrates to present Ag to naïve T cells. In a revised view (B), physically different DCs within the same subset detect pathogen directly and secrete inflammatory cytokines (“detector” DCs), whereas “presenter” DCs may receive pathogen-derived Ag indirectly through other cells, migrate, and present it (“presenter” DCs).

Figure 3.

Dendritic cells induce peripheral tolerance or immunity by directing the fate of antigen-specific T cells. Presentation by steady-state DCs of weakly agonistic self-peptides maintains tonic Ag receptor signaling and responsiveness of both normal and self-reactive T cells. Strongly agonistic self-peptides may tolerize self-reactive T cells when presented by steady-state DCs, whereas foreign peptides presented by activated DCs induce T-cell priming. The loss of DCs would lead to an unresponsive state in both normal and self-reactive T cells, and prevent self- as well as foreign Ag-specific T-cell responses.