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Colonna and colleagues show that the clock genes encoding REV-ERBα and REV-ERBβ maintain ILC3 functions in the gut by controlling the expression of RORγt.

T_FH cells that express IL-13 are associated with high-affinity IgE responses, but factors controlling their development, transcriptional programming and exact function have remained unclear. Here, Chandrakar et al. find that the transcription factor JunB is required for T_FH13 cell maintenance and that T_FH13 cells producing IL-21 drive broad germinal center responses to allergen-specific IgG and IgE.

T cell immunoglobulin and mucin domain–containing 3 (Tim-3) is an inhibitory receptor that is expressed on exhausted T cells and suppresses T helper type 1 (T_H1) responses. Vijay Kuchroo and his colleagues show that human leukocyte antigen B (HLA-B)-associated transcript 3 (Bat3) binds intracellularly to Tim-3 and represses its function. Bat3 knockdown suppresses the development of experimental autoimmune encephalomyelitis and induces an exhaustion-like phenotype in T cells.

Deficiency in Wiskott-Aldrich syndrome protein (WASP) has been associated with autoimmune colitis, but the underlying mechanism is still unclear. Here the authors show that WASP deficiency is associated with defective WASP/DOCK8 complex formation, altered IL-10 signalling, and impaired anti-inflammatory macrophage functions.

Neuromedin receptor NMUR1 is specifically expressed by a subpopulation of type 2 innate lymphoid cells and promotes the inflammatory response of these cells in response to allergens, indicating the importance of neuro-immune crosstalk in allergic responses.

The TIM (T-cell immunoglobulin domain and mucin domain) proteins are emerging as important regulators of immune responses. The recent identification of TIM-protein expression by antigen-presenting cells and new TIM-protein ligands is revealing new roles for these proteins.

Manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth.

The costimulatory molecule ICOS is important for the development of both interleukin 17–producing and follicular T helper cells. Kuchroo and colleagues find that ICOS induces the transcription factor c-Maf, which regulates the population expansion of both helper cell types.

Foxp3 is required for the generation and function of regulatory T cells. Kuchroo and colleagues find that interleukin 4 blocks the generation of these cells but promotes T helper cells that produce interleukins 9 and 10.

Type 1 regulatory T cells control autoinflammatory diseases. In two linked papers, groups led by Kuchroo and Quintana demonstrate the role of the aryl hydrocarbon receptor in the differentiation of these cells.

The T_H17 pathway is thought to contribute to the pathogenesis of a number of human autoimmune diseases. This study examines which cytokines are required for the production of IL-17A by memory and naive human CD4⁺ T cells.

Follicular regulatory T cells (T_FR cells) inhibit follicular helper T cell (T_FH cell)-mediated antibody production. Sharpe and colleagues show that T_FR cells induce a distinct suppressive state in T_FH cells and B cells that can be reversed by the cytokine IL-21.

RAMP3, a component of the receptor for the neuropeptide CGRP, has a cell-intrinsic role in T helper type 1 cell fate determination.

The immune-checkpoint molecule TIM-3 regulates microglial homeostasis, and its microglial-specific deletion reduced cognitive impairment in a mouse model of Alzheimer’s disease.

Inflammatory monocytes in the brain meninges promote stress-induced fear behaviour, and the pathways involved can be modulated using psychedelic compounds.

Tim-3 is an inhibitory molecule that suppresses T-cell responses. Here the authors show that the cytokine IL-27, acting through the transcription factor NFIL3, induces Tim-3 in vivo, and that IL-27-conditioned Th1 cells have poor effector function.

Tr1 cells have potent regulatory effects in vitro and in vivo. Kuchroo and colleagues comprehensively describe the epigenetic, transcriptional and gene regulatory landscape that is essential for Tr1 cell differentiation.

Exposure to interleukin 23 (IL-23) is required for the induction of pathogenic T_H17 cells. Kuchroo and colleagues show that IL-23-dependent induction of the cytokine TGF-β3 produces a molecular signature characteristic of highly pathogenic T_H17 cells.

Mouse genetic studies and single-cell transcriptome analysis demonstrate that TIM-3 on dendritic cells has a key role in regulating antitumour immunity via inflammasome activation and is a potential target for anticancer therapy.

Here, the authors show that deletion of Pglyrp1 promotes antitumor immunity owing to its inhibitory function in CD8⁺ T cells and that targeting it can inhibit development of autoimmune neuroinflammation. These findings indicate that PGLYRP1 might be a target for immunotherapy.

Regulating the balance between T_H17 cells that drive autoimmune inflammation and nonpathogenic T_H17 cells is critical for limiting autoimmune pathology. Here, the authors extensively characterize these two cell states at the transcriptomic and epigenetic levels and show how BACH2 is protective in this context.

Under most circumstances, Foxp3⁺ regulatory T (T_reg) cells are a stable T cell population essential for maintaining self-tolerance. A study now shows that the inflammatory environment in autoimmune arthritis induces conversion of a subset of Foxp3⁺ T cells into interleukin-17–producing cells that contribute to disease pathogenesis (pages 62–68).

Transcriptional profiling of developing T_H17 cells identifies serum glucocorticoid kinase 1 (SGK1) as an essential node downstream of IL-23 signalling, and transcriptional analysis shows that a modest increase in salt concentration induces SGK1 expression, promotes IL-23 receptor expression and enhances T_H17 cell differentiation, accelerating the development of autoimmunity.

How do T cells that are specific for pancreatic islet cell antigens cause diabetes? A recent paper in Nature provides evidence from NOD mice that the killer T cells responsible increase their avidity as the disease progresses—removing the high avidity clones prevents disease.

Kuchroo and colleagues review T_H17 cell heterogeneity and discuss how this affects the function of T_H17 cells in homeostasis and disease.

Lactate produced by dendritic cells (DCs) suppresses T-cell-mediated autoimmunity through a mechanism in which lactate activates HIF-1α–NDUFA4L2 signalling in DCs and thereby limits DC-mediated pro-inflammatory responses such as the development of encephalitogenic T cells.

T_H17 cells are a recently defined subset of pro-inflammatory helper T cells that are induced by the cytokines IL-6 and transforming growth factor (TGF)-β. T_H17 can also be induced by an alternative pathway in which TGF-β cooperates with IL-21.

A module of co-inhibitory T cell receptors, driven by the cytokine IL-27, is identified in mice that is regulated by the transcription factors PRDM1 and c-MAF.

A global view of the genetic networks regulating the differentiation of T_H17 cells is presented, based on temporal expression profiling, computational network reconstruction and validation of predicted interactions by nanowire-mediated siRNA perturbation.

Here Ramanan and colleagues provide an analysis of mammary T cells during late pregnancy and lactation. This revealed an increase in intraepithelial lymphocytes in the lactating mammary gland, which was driven by thymic and intestinal inputs and was sensitive to changes in the microbiota

In this issue, Thomas Kupper and colleagues report that mice deficient for ROR-γ or interleukin-23 (IL-23) receptor showed impaired melanoma growth. Tumor growth inhibition was dependent in part on IL-9 and T helper type 9 (T_H9) cells. Moreover, the authors showed that IL-9 acts on mast cells rather than T or B cells to mediate its antitumor effects and that T_H9 cells are present in human blood and skin, suggesting that a role for T_H9 cells in human tumor immunity should be explored.

T_H17 cells contribute to anti-fungal and anti-bacterial adaptive immune responses. Sallusto and colleagues show that the transcription factor c-Maf has an immunoregulatory role in directing gene expression and tissue residency in human IL-10⁺ T_H17 cell subsets.