Highlights d Environmental stiffness promotes DC inflammatory function d Tension primes DC metabolism, even without pattern recognition receptor input d TAZ bridges mechanosensory signals to DC metabolism and function d Tension directs phenotypes of human monocyte-derived DCs

Plasmacytoid dendritic cells (pDCs) are known mainly for their secretion of type I IFN upon viral encounter. We describe a CD2 hi CD5 + CD81 + pDC subset, distinguished by prominent dendrites and a mature phenotype, in human blood, bone marrow, and tonsil, which can be generated from CD34 + progenitors. These CD2 hi CD5 + CD81 + cells express classical pDC markers, as well as the toll-like receptors that enable conventional pDCs to respond to viral infection. However, their gene expression profile is distinct, and they produce little or no type I IFN upon stimulation with CpG oligonucleotides, likely due to their diminished expression of IFN regulatory factor 7. A similar population of CD5 + CD81 + pDCs is present in mice and also does not produce type I IFN after CpG stimulation. In contrast to conventional CD5 − CD81 − pDCs, human CD5 + CD81 + pDCs are potent stimulators of B-cell activation and antibody production and strong inducers of T-cell proliferation and Treg formation. These findings reveal the presence of a discrete pDC population that does not produce type I IFN and yet mediates important immune functions previously attributed to all pDCs.P lasmacytoid dendritic cells (pDCs) are a distinct lineage of bone-marrow-derived cells that reside mainly in blood and lymphoid organs in the steady state, but can also be found in sites of infection, inflammation, and cancer (1). As one of the two principal lineages of dendritic cells, pDCs diverge from conventional DCs (cDCs) during maturation in the bone marrow and are recognized mainly for their rapid and massive production of type I IFN (IFNα/β) in response to viral infection (2). Although generally viewed as weak antigen-presenting cells by comparison with cDCs, pDCs interact with many types of cells, such as NK cells, cDCs, T cells, and B cells through their secretion of cytokines and chemokines in addition to type I IFN, as well as through their expression of various costimulatory molecules (3, 4). Thus, pDCs are capable of activating CD4 + helper and regulatory T cells and CD8 + cytotoxic T cells (5-16). They can also stimulate B-cell activation, differentiation into plasma cells, and antibody production through mechanisms that are not yet completely understood (17)(18)(19)(20)(21)(22).Whether the diverse functions of pDCs are mediated by the same cells responding to different environmental cues or by distinct preprogrammed subsets or lineages is not clear, although several reports suggest the existence of phenotypically distinct subpopulations of pDCs in mice (23-25) and humans (26-30). Surface expression of CD2 divides human pDCs into two distinct subsets. Whereas both CD2 lo and CD2 hi pDCs produce type I IFN, the CD2 hi subset secretes more IL12p40, triggers more T-cell proliferation (26), and is relatively resistant to apoptosis on the basis of higher BCL2 expression (28). Here we show that CD2 hi pDCs contain a unique subpopulation that expresses CD5 and CD81. Unlike CD2 hi CD5 − CD81 − pDCs, CD2 hi CD5 + CD81 + pDCs fail to produce type 1 IFN but ...

Interleukin 23 (IL-23) is a new member of the IL-12 family that plays a critical role in promoting the proliferation of memory T helper 1 cells. The heterodimerized IL-23 receptor is composed of a shared IL-12 receptor beta 1 (IL-12Rbeta1) and an IL-12Rbeta2-related molecule called IL-23R. The standard form of IL-23R is encoded by at least 12 exons. Here, we demonstrate that at least six spliced isoforms of IL-23R (IL-23R1 to 6) can be generated through alternative splicing. The splicing strategies for the IL-23R gene are complicated and most often result in the deletion of exon 7 and/or exon 10. Translation prediction revealed that these spliced variants result in either premature termination to give rise to a diverse form of receptor ectodomain, or a frameshift to generate various lengths of the IL-23R endodomain. Differential expressions of IL-23R spliced variants are observed in natural killer and CD3+ CD4+ T cells. The expressions of these spliced variants are also prevalently and complicatedly regulated in tumor cell lines. Interestingly, only IL-23R2 and/or IL-23R4 variants are predominantly detected in certain human lung carcinomas, but not in their resected normal margin tissues. Thus, our results indicate that the regulation of alternative splicing on the IL-23R gene is complicated, and the preferential expression of certain IL-23R spliced variants may be a contributive factor to the pathogenesis of certain cancers.

The combination of total lymphoid irradiation and anti-T-cell antibodies safely induces immune tolerance to combined hematopoietic cell and organ allografts in humans. Our mouse model required host natural killer T (NKT) cells to induce tolerance. Because NKT cells normally depend on signals from CD8 dendritic cells (DCs) for their activation, we used the mouse model to test the hypothesis that, after lymphoid irradiation, host CD8 DCs play a requisite role in tolerance induction through interactions with NKT cells. Selective deficiency of either CD8 DCs or NKT cells abrogated chimerism and organ graft acceptance. After radiation, the CD8 DCs increased expression of surface molecules required for NKT and apoptotic cell interactions and developed suppressive immune functions, including production of indoleamine 2,3-deoxygenase. Injection of naive mice with apoptotic spleen cells generated by irradiation led to DC changes similar to those induced by lymphoid radiation, suggesting that apoptotic body ingestion by CD8 DCs initiates tolerance induction. Tolerogenic CD8 DCs induced the development of tolerogenic NKT cells with a marked T helper 2 cell bias that, in turn, regulated the differentiation of the DCs and suppressed rejection of the transplants. Thus, reciprocal interactions between CD8 DCs and invariant NKT cells are required for tolerance induction in this system that was translated into a successful clinical protocol.

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