A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation.

The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, Gclc deficiency did not alter cytokine secretion; however, C.

SKI Regulates Medullary Thymic Epithelial Cell Differentiation to Control Peripheral T Cell Responses in Mice.

The thymus is an important site for the establishment of an appropriate immune response through positive and negative selection of developing T cells. During selection, developing T cells interact with cortical and medullary thymic epithelial cells (TECs), termed cTECs and mTECs, respectively. Using a Foxn1Cre+/-SKIfl/fl mouse model, we found that TEC-specific deletion of SKI reduced the mTEC compartment in the thymus and that tissue-restricted Ag expression in mTECs was altered.

A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation.

Although the intestinal tract is a major site of reactive oxygen species (ROS) generation, the mechanisms by which antioxidant defense in gut T cells contribute to intestinal homeostasis are currently unknown. Here we show, using T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (), that the ensuing loss of glutathione (GSH) impairs the production of gut-protective IL-22 by Th17 cells within the lamina propria. Although ablation does not affect T cell cytokine secretion in the gut of mice at steady-state, infection with increases ROS, inhibits mitochondrial gene expression and mitochondrial function in -deficient Th17 cells.

Profiling of Tregs across tissues reveals plasticity in ST2 expression and hierarchies in tissue-specific phenotypes.

Foxp3 regulatory T cells (Tregs) are critical mediators of peripheral tolerance and immune homeostasis and exert tissue-specific functions. In many nonlymphoid tissues, Tregs show enriched expression of the IL-33 receptor ST2. Through comprehensive profiling of murine ST2 and ST2 Tregs, we found that Treg transcriptomes and phenotypes formed a hierarchical relationship across tissues.

FOXP3 exon 2 controls T stability and autoimmunity.

Differing from the mouse gene that encodes only one protein product, human encodes two major isoforms through alternative splicing-a longer isoform (FOXP3 FL) containing all the coding exons and a shorter isoform lacking the amino acids encoded by exon 2 (FOXP3 ΔE2). The two isoforms are naturally expressed in humans, yet their differences in controlling regulatory T cell phenotype and functionality remain unclear. In this study, we show that patients expressing only the shorter isoform fail to maintain self-tolerance and develop immunodeficiency, polyendocrinopathy, and enteropathy X-linked (IPEX) syndrome.

Fate-Mapping of GM-CSF Expression Identifies a Discrete Subset of Inflammation-Driving T Helper Cells Regulated by Cytokines IL-23 and IL-1β.

Pathogenic lymphocytes initiate the development of chronic inflammatory diseases. The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) (encoded by Csf2) is a key communicator between pathogenic lymphocytes and tissue-invading inflammatory phagocytes. However, the molecular properties of GM-CSF-producing cells and the mode of Csf2 regulation in vivo remain unclear.

Graft-versus-host disease, but not graft-versus-leukemia immunity, is mediated by GM-CSF-licensed myeloid cells.

Allogeneic hematopoietic cell transplantation (allo-HCT) not only is an effective treatment for several hematologic malignancies but can also result in potentially life-threatening graft-versus-host disease (GvHD). GvHD is caused by T cells within the allograft attacking nonmalignant host tissues; however, these same T cells mediate the therapeutic graft-versus-leukemia (GvL) response. Thus, there is an urgent need to understand how to mechanistically uncouple GvL from GvHD.

Erratum: Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.

This corrects the article DOI: 10.1038/nm.4484.

Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.

Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD leukemia cells. This synergized with the allogeneic CD8 T cell response, leading to long-term survival in six mouse models of FLT3-ITD AML.

Dysregulation of the Cytokine GM-CSF Induces Spontaneous Phagocyte Invasion and Immunopathology in the Central Nervous System.

Chronic inflammatory diseases are influenced by dysregulation of cytokines. Among them, granulocyte macrophage colony stimulating factor (GM-CSF) is crucial for the pathogenic function of T cells in preclinical models of autoimmunity. To study the impact of dysregulated GM-CSF expression in vivo, we generated a transgenic mouse line allowing the induction of GM-CSF expression in mature, peripheral helper T (Th) cells.

Cytokine networks in neuroinflammation.

Cytokines provide cells with the ability to communicate with one another and orchestrate complex multicellular behaviour. There is an emerging understanding of the role that cytokines play in normal homeostatic tissue function and how dysregulation of these cytokine networks is associated with pathological conditions. The central nervous system (CNS), where few blood-borne immune cells circulate, seems to be particularly vulnerable to dysregulated cytokine networks.

GM-CSF in Neuroinflammation: Licensing Myeloid Cells for Tissue Damage.

Multiple sclerosis (MS) is the prototypical inflammatory disease of the central nervous system (CNS). MS lesions harbor different immune cells, but the contribution of individual cell types to disease etiology and progression is not well understood. In experimental autoimmune encephalomyelitis (EAE), auto-reactive helper T (Th) cells instigate CNS inflammation by acting on myeloid cells via the production of granulocyte-macrophage colony-stimulating factor (GM-CSF).

Helicobacter pylori-specific protection against inflammatory bowel disease requires the NLRP3 inflammasome and IL-18.

Background: The Gram-negative bacterium Helicobacter pylori is a constituent of the human gastric microbiota. Chronic infection with H. pylori causes gastritis and predisposes to gastric carcinoma but has also been inversely linked to various allergic and chronic inflammatory conditions.

T-bet or not T-bet: taking the last bow on the autoimmunity stage.

The search for the encephalitogenic factor driving pathogenic T cells in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis (MS), and psoriasis has proven to be a long and difficult mission, which is not yet completed. In this issue of the European Journal of Immunology, the importance of the transcription factor T-bet, previously shown to be essential for the induction of autoimmune disease in mice, is challenged. Two independent groups, O'Connor et al.