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In this issue of Immunity, Silver et al. (2012) provide evidence that murine Toll-like receptor 9 (TLR9) expression and function in innate and adaptive immunity is controlled by the circadian cycle.
Microbial penetration of the intestinal epithelial barrier triggers inflammatory responses that include induction of the bactericidal C-type lectin RegIIIγ. Systemic administration of flagellin, a bacterial protein that stimulates Toll-like receptor 5 (TLR5), induces epithelial expression of RegIIIγ and protects mice from intestinal colonization with antibiotic-resistant bacteria. Flagellin-induced...
Interleukin-1β (IL-1β) is a potent inflammatory cytokine that is usually cleaved and activated by inflammasome-associated caspase-1. To determine whether IL-1β activation is regulated by inhibitor of apoptosis (IAP) proteins, we treated macrophages with an IAP-antagonist “Smac mimetic” compound or genetically deleted the genes that encode the three IAP family members cIAP1, cIAP2, and XIAP. After...
In this issue of Immunity, den Braber et al. (2012) highlight differences in naive T cell lifespan between mice and humans. Their data suggest that mechanisms of naive T cell maintenance may differ between mice and men.
Inhibitors of apoptosis proteins (IAPs) are important regulators of both cell death and inflammation. In this issue of Immunity, Vince et al. (2012) report that inhibition of IAPs results in the processing and secretion of IL-1β through RIP3-mediated caspase-1- and caspase-8-dependent pathways.
Follicular helper T cells (Tfh cells) are the major producers of interleukin-4 (IL-4) in secondary lymphoid organs where humoral immune responses develop. Il4 regulation in Tfh cells appears distinct from the classical T helper 2 (Th2) cell pathway, but the underlying molecular mechanisms remain largely unknown. We found that hypersensitivity site V (HS V; also known as CNS2), a 3′ enhancer in the...
The emerging notion of environment-induced reprogramming of Foxp3 + regulatory T (Treg) cells into helper T (Th) cells remains controversial. By genetic fate mapping or adoptive transfers, we have identified a minor population of nonregulatory Foxp3 + T cells exhibiting promiscuous and transient Foxp3 expression, which gave rise to Foxp3 − (“exFoxp3”) Th cells and selectively...
T cell development occurs in the thymus. The thymic microenvironment attracts hematopoietic progenitors, specifies them toward the T cell lineage, and orchestrates their differentiation and egress into the periphery. The anatomical location of the thymus and the intrauterine development of mouse embryos have so far precluded a direct visualization of the initial steps of thymopoiesis. Here, we describe...
Regulatory T (Treg) cells are thought to be susceptible to conversion into effector T cells. In this issue of Immunity, Miyao et al. (2012) provide evidence that the apparent plasticity of murine Foxp3 + Treg cells is largely restricted to a defined subset of poorly committed Foxp3 + cells.
The Toll-like receptor adaptor protein MyD88 is essential for the regulation of intestinal homeostasis in mammals. In this study, we determined that Myd88-deficient mice are susceptible to colonic damage that is induced by dextran sulfate sodium (DSS) administration resulting from uncontrolled dissemination of intestinal commensal bacteria. The DSS-induced mortality of Myd88-deficient mice was completely...
Janus kinases (JAKs) are key effectors in controlling immune responses and maintaining hematopoiesis. SOCS3 (suppressor of cytokine signaling-3) is a major regulator of JAK signaling and here we investigate the molecular basis of its mechanism of action. We found that SOCS3 bound and directly inhibited the catalytic domains of JAK1, JAK2, and TYK2 but not JAK3 via an evolutionarily conserved motif...
Interferons (IFNs) were discovered as cytokines induced during and protecting from viral infection. They have been documented to play essential roles in numerous physiological processes beyond antiviral and antimicrobial defense, including immunomodulation, cell cycle regulation, cell survival, and cell differentiation. Recent data have also uncovered a potentially darker side to IFN, including roles...
A main role for interleukin-4 (IL-4) is in humoral immunity, and follicular helper CD4 + T (Tfh) cells may be an intrinsic IL-4 source. Here we demonstrate that conserved noncoding sequence 2 (CNS2) is an essential enhancer element for IL-4 expression in Tfh cells but not in Th2 cells. Mice with a CNS2 deletion had a reduction in IgG1 and IgE production and in IL-4 expression in Tfh cells...
Parallels between T cell kinetics in mice and men have fueled the idea that a young mouse is a good model system for a young human, and an old mouse, for an elderly human. By combining in vivo kinetic labeling using deuterated water, thymectomy experiments, analysis of T cell receptor excision circles and CD31 expression, and mathematical modeling, we have quantified the contribution of thymus output...
The reason why CD4 + T helper 17 (Th17) cells, despite their well-known pathogenic role in chronic inflammatory disorders, are very rare in the inflammatory sites remains unclear. We demonstrate that human Th17 cells exhibit low ability to proliferate and to produce the T cell growth factor interleukin-2 (IL-2), in response to combined CD3 and CD28 stimulation. This was due to the upregulated...
The natural helper (NH) cell comprises a newly identified Th2 cell-type innate lymphocyte population. In this issue of Immunity, Halim et al. (2012) provide evidence that NH cells reside in the lung and play a critical role in protease allergen-induced airway inflammation.
Neutralizing antibodies have been thought to be required for protection against acutely cytopathic viruses, such as the neurotropic vesicular stomatitis virus (VSV). Utilizing mice that possess B cells but lack antibodies, we show here that survival upon subcutaneous (s.c.) VSV challenge was independent of neutralizing antibody production or cell-mediated adaptive immunity. However, B cells were absolutely...
Central tolerance can be mediated by peripheral dendritic cells (DCs) that transport innocuous antigens (Ags) to the thymus for presentation to developing T cells, but the responsible DC subsets remained poorly defined. Immature plasmacytoid DCs (pDCs) express CCR9, a chemokine receptor involved in migration of T cell precursors to the thymus. We show here that CCR9 mediated efficient thymic entry...
In this issue of Immunity, Shan et al. (2012) explore the elimination of cells latently infected with HIV and the potential implications for strategies to eradicate the virus from infected patients.
Numerous regulatory programs have been identified that contribute to the restoration of homeostasis at the conclusion of immune responses and to safeguarding against the detrimental effects of chronic inflammation and autoimmune pathology. Malignant cells may usurp these pathways to create immunosuppressive networks that thwart antitumor responses. Herein we review the role of endogenous lectins (C-type...
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