Immunological Reviews

Summary:  X‐box binding protein‐1 (XBP‐1) is a transcription factor essential for plasma cell differentiation. XBP‐1 transcripts are found at high levels in plasma cells from rheumatoid synovium and myeloma cell lines. Lymphoid chimeras deficient in XBP‐1 have a profound defect in plasma cell differentiation, with few plasma cells in their periphery and severely reduced serum immunoglobulin levels. When introduced into B‐lineage cells, XBP‐1 initiates plasma cell differentiation. XBP‐1 is also the mammalian homologue of the yeast transcription factor Hac1p, an important component of the unfolded protein response (UPR). The UPR allows cells to tolerate conditions of endoplasmic reticulum (ER) stress caused by misfolded proteins. Studies examining the relationship between plasma cell differentiation, XBP‐1, and the UPR demonstrate that this novel signaling system is vital for plasma cell differentiation. Signals that induce plasma cell differentiation and the UPR cooperate via XBP‐1 to induce terminal B‐cell differentiation. Additionally, XBP‐1 plays an important role in the regulation of interleukin‐6 production, a cytokine essential for plasma cell survival.

Summary:  Plasmacytoid dendritic cells (pDCs) are bone marrow‐derived cells that secrete large amounts of type I interferon (IFN) in response to viruses. Type I IFNs are pleiotropic cytokines with antiviral activity that also enhance innate and adaptive immune responses. Viruses trigger activation of pDCs and type I IFN responses mainly through the Toll‐like receptor pathway. However, a variety of activating and inhibitory pDC receptors fine tune the amplitude of type I IFN responses. Chronic activation and secretion of type I IFN in the absence of infection can promote autoimmune diseases. Furthermore, while activated pDCs promote immunity and autoimmunity, resting or alternatively activated pDCs may be tolerogenic. The various roles of pDCs have been extensively studied in vitro and in vivo with depleting antibodies. However, depleting antibodies cross‐react with other cell types that are critical for eliciting protective immunity, potentially yielding ambiguous phenotypes. Here we discuss new approaches to assess pDC functions in vivo and provide preliminary data on their potential roles during viral infections. Such approaches would also prove useful in the more specific evaluation of how pDCs mediate tolerance and autoimmunity. Finally, we discuss the emergent role of pDCs and one of their receptors, tetherin, in human immunodeficiency virus pathogenesis.

Summary:  Mouse lymphoid tissues contain a subset of dendritic cells (DCs) expressing CD8α together with a pattern of other surface molecules that distinguishes them from other DCs. These molecules include particular Toll‐like receptor and C‐type lectin pattern recognition receptors. A similar DC subset, although lacking CD8 expression, exists in humans. The mouse CD8⁺ DCs are non‐migrating resident DCs derived from a precursor, distinct from monocytes, that continuously seeds the lymphoid organs from bone marrow. They differ in several key functions from their CD8⁻ DC neighbors. They efficiently cross‐present exogenous cell‐bound and soluble antigens on major histocompatibility complex class I. On activation, they are major producers of interleukin‐12 and stimulate inflammatory responses. In steady state, they have immune regulatory properties and help maintain tolerance to self‐tissues. During infection with intracellular pathogens, they become major presenters of pathogen antigens, promoting CD8⁺ T‐cell responses to the invading pathogens. Targeting vaccine antigens to the CD8⁺ DCs has proved an effective way to induce cytotoxic T lymphocytes and antibody responses.

During the last decades, many studies have investigated the transcriptional and epigenetic regulation of lineage decision in the hematopoietic system. These efforts led to a model in which extrinsic signals and intrinsic cues establish a permissive chromatin context upon which a regulatory network of transcription factors and epigenetic modifiers act to guide the differentiation of hematopoietic lineages. These networks include lineage‐specific factors that further modify the epigenetic landscape and promote the generation of specific cell types. The process of B lymphopoiesis requires a set of transcription factors, including Ikaros, PU.1, E2A, and FoxO1 to ‘prime’ cis‐regulatory regions for subsequent activation by the B‐lineage‐specific transcription factors EBF1 and Pax‐5. The expression of EBF1 is initiated by the combined action of E2A and FoxO1, and it is further enhanced and maintained by several positive feedback loops that include Pax‐5 and IL‐7 signaling. EBF1 acts in concert with Ikaros, PU.1, Runx1, E2A, FoxO1, and Pax‐5 to establish the B cell‐specific transcription profile. EBF1 and Pax‐5 also collaborate to repress alternative cell fates and lock cells into the B‐lineage fate. In addition to the functions of EBF1 in establishing and maintaining B‐cell identity, EBF1 is required to coordinate differentiation with cell proliferation and survival.

Inflammatory caspases play a central role in innate immunity by responding to cytosolic signals and initiating a twofold response. First, caspase‐1 induces the activation and secretion of the two prominent pro‐inflammatory cytokines, interleukin‐1β (IL‐1β) and IL‐18. Second, either caspase‐1 or caspase‐11 can trigger a form of lytic, programmed cell death called pyroptosis. Pyroptosis operates to remove the replication niche of intracellular pathogens, making them susceptible to phagocytosis and killing by a secondary phagocyte. However, aberrant, systemic activation of pyroptosis in vivo may contribute to sepsis. Emphasizing the efficiency of inflammasome detection of microbial infections, many pathogens have evolved to avoid or subvert pyroptosis. This review focuses on molecular and morphological characteristics of pyroptosis and the individual inflammasomes and their contribution to defense against infection in mice and humans.

Roles for cell death in development, homeostasis, and the control of infections and cancer have long been recognized. Although excessive cell damage results in passive necrosis, cells can be triggered to engage molecular programs that result in cell death. Such triggers include cellular stress, oncogenic signals that engage tumor suppressor mechanisms, pathogen insults, and immune mechanisms. The best‐known forms of programmed cell death are apoptosis and a recently recognized regulated necrosis termed necroptosis. Of the two best understood pathways of apoptosis, the extrinsic and intrinsic (mitochondrial) pathways, the former is induced by the ligation of death receptors, a subset of the TNF receptor (TNFR) superfamily. Ligation of these death receptors can also induce necroptosis. The extrinsic apoptosis and necroptosis pathways regulate each other and their balance determines whether cells live. Integral in the regulation and initiation of death receptor‐mediated activation of programmed cell death is the aspartate‐specific cysteine protease (caspase)‐8. This review describes the role of caspase‐8 in the initiation of extrinsic apoptosis execution and the mechanism by which caspase‐8 inhibits necroptosis. The importance of caspase‐8 in the development and homeostasis and the way that dysfunctional caspase‐8 may contribute to the development of malignancies in mice and humans are also explored.