Radiotherapy is an important treatment for cancer. The main mode of action is thought to be the irreversible damage to tumor cell DNA, but there is evidence that irradiation mobilizes tumor-specific immunity, and recent studies showed that the efficacy of high-dose radiotherapy depends on the presence of CD8+ T cells. We show in this study that the efficacy of radiotherapy given as a single, high dose (10 Gy) crucially depends on dendritic cells and CD8+ T cells, whereas CD4+ T cells or macrophages are dispensable. We show that local high-dose irradiation results in activation of tumor-associated dendritic cells that in turn support tumor-specific effector CD8+ T cells, thus identifying the mechanism that underlies radiotherapy-induced mobilization of tumor-specific immunity. We propose that in the absence of irradiation, the activation status of dendritic cells rather than the amount of tumor-derived Ag is the bottleneck, which precludes efficient anti-tumor immunity.

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Environmental signals shape host physiology and fitness. Microbiota-derived cues are required to program conventional dendritic cells (cDCs) during the steady state so that they can promptly respond and initiate adaptive immune responses when encountering pathogens. However, the molecular underpinnings of microbiota-guided instructive programs are not well understood. Here, we report that the indigenous microbiota controls constitutive production of type I interferons (IFN-I) by plasmacytoid DCs. Using genome-wide analysis of transcriptional and epigenetic regulomes of cDCs from germ-free and IFN-I receptor (IFNAR)-deficient mice, we found that tonic IFNAR signaling instructs a specific epigenomic and metabolic basal state that poises cDCs for future pathogen combat. However, such beneficial biological function comes with a trade-off. Instructed cDCs can prime T cell responses against harmless peripheral antigens when removing roadblocks of peripheral tolerance. Our data provide fresh insights into the evolutionary trade-offs that come with successful adaptation of vertebrates to their microbial environment.

The quality of the adaptive immune response depends on the differentiation of distinct CD4(+) helper T cell subsets, and the magnitude of an immune response is controlled by CD4(+)Foxp3(+) regulatory T cells (Treg cells). However, how a tissue- and cell type-specific suppressor program of Treg cells is mechanistically orchestrated has remained largely unexplored. Through the use of Treg cell-specific gene targeting, we found that the suppression of allergic immune responses in the lungs mediated by T helper type 2 (TH2) cells was dependent on the activity of the protein kinase CK2. Genetic ablation of the β-subunit of CK2 specifically in Treg cells resulted in the proliferation of a hitherto-unexplored ILT3(+) Treg cell subpopulation that was unable to control the maturation of IRF4(+)PD-L2(+) dendritic cells required for the development of TH2 responses in vivo.

Resting dendritic cells (DCs) induce tolerance of peripheral T cells that have escaped thymic negative selection and thus contribute significantly to protection against autoimmunity. We recently showed that CD4 + Foxp3+ regulatory T cells (Tregs) are important for maintaining the steady-state phenotype of DCs and their tolerizing capacity in vivo. We now provide evidence that DC activation in the absence of Tregs is a direct consequence of missing DC-Treg interactions rather than being secondary to generalized autoimmunity in Treg-less mice. We show that DCs that lack MHC class II and thus cannot make cognate interactions with CD4 + T cells are completely unable to induce peripheral CD8 + T-cell tolerance. Consequently, mice in which interactions between DC and CD4 + T cells are not possible develop spontaneous and fatal cytotoxic T lymphocyte-mediated autoimmunity. DCs are bone marrow (BM)-derived, short-lived cells that play a key role in regulating immune responses. They are located at low frequency in lymphoid and nonlymphoid organs throughout the body, where they act as sentinels for invading pathogens. On recognition of pathogen-associated cues, DCs undergo a series of functional changes termed maturation, which is characterized by the up-regulation of costimulatory molecules such as CD80, CD86, and CD70, by the production of cytokines, such as IL-12, and by the expression of homing receptors, such as CCR7, that direct DC migration into the T-cell areas of secondary lymphoid organs. Together these changes allow DCs to efficiently activate naive T cells.Over the past decade, it has become clear that steady-state DCs play an important role in the maintenance of self-tolerance (1-3) and T-cell responsiveness (4). Because DCs can either prime or tolerize naive T cells, depending on their activation status, they are master regulators of adaptive immunity. How the maturation status of DCs translates into differential effects on naive T cells involves a variety of costimulatory and coinhibitory interactions between T cells and DCs. For example, we showed that tolerance induction depends on PD-1 and CTLA-4 (5), whereas blockade of CD70, a costimulatory molecule that is upregulated on activated DCs, prevents priming of CD8 + T cells even in the context of an infection (6). Along the same line, constitutive transgenic expression of CD70 on all DCs prevents the induction of tolerance and results in priming of a functional T-cell response by steady-state DCs (7).DC maturation can be triggered by numerous exogenous and endogenous stimuli that are usually associated with infection, inflammation, or damage (8 (10)(11)(12)(13)(14). Tregs may control self-reactive T-cell responses by direct interaction with conventional T cells or, alternatively, may act on DCs (15). Evidence for the latter comes from experiments in which depletion of Tregs results in Flt3-dependent increases in the number of DCs as well as in DC activation (9,11,16).When we combined the DIETER model of peripheral tolerance induction by steady-state DCs a...