Local administration of regulatory T cells promotes tissue healing.

Regulatory T cells (Tregs) are crucial immune cells for tissue repair and regeneration. However, their potential as a cell-based regenerative therapy is not yet fully understood. Here, we show that local delivery of exogenous Tregs into injured mouse bone, muscle, and skin greatly enhances tissue healing.

Tregs delivered post-myocardial infarction adopt an injury-specific phenotype promoting cardiac repair via macrophages in mice.

Regulatory T cells (Tregs) are key immune regulators that have shown promise in enhancing cardiac repair post-MI, although the mechanisms remain elusive. Here, we show that rapidly increasing Treg number in the circulation post-MI via systemic administration of exogenous Tregs improves cardiac function in male mice, by limiting cardiomyocyte death and reducing fibrosis. Mechanistically, exogenous Tregs quickly home to the infarcted heart and adopt an injury-specific transcriptome that mediates repair by modulating monocytes/macrophages.

Transcriptional and hormonal control of adipose Treg heterogeneity and function.

Adipose tissue stores excess energy and produces a broad range of factors that regulate multiple physiological processes including systemic energy homeostasis. Visceral adipose tissue (VAT) plays a particularly important role in glucose metabolism as its endocrine function underpins food uptake and energy expenditure. Caloric excess triggers VAT inflammation which can impair insulin sensitivity and cause metabolic deregulation.

Two regulatory T cell populations in the visceral adipose tissue shape systemic metabolism.

Visceral adipose tissue (VAT) is an energy store and endocrine organ critical for metabolic homeostasis. Regulatory T (T) cells restrain inflammation to preserve VAT homeostasis and glucose tolerance. Here, we show that the VAT harbors two distinct T cell populations: prototypical serum stimulation 2-positive (ST2) T cells that are enriched in males and a previously uncharacterized population of C-X-C motif chemokine receptor 3-positive (CXCR3) T cells that are enriched in females.

Role reversals: non-canonical roles for immune and non-immune cells in the gut.

The intestine is home to an intertwined network of epithelial, immune, and neuronal cells as well as the microbiome, with implications for immunity, systemic metabolism, and behavior. While the complexity of this microenvironment has long since been acknowledged, recent technological advances have propelled our understanding to an unprecedented level. Notably, the microbiota and non-immune or structural cells have emerged as important conductors of intestinal immunity, and by contrast, cells of both the innate and adaptive immune systems have demonstrated non-canonical roles in tissue repair and metabolism.

Gut microbiota - a double-edged sword in cancer immunotherapy.

Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, many patients fail to respond to this therapy or experience side effects. Recently, gut microbiota have emerged as a key determinant of ICB efficacy and toxicity, making manipulation of the microbiome a novel therapeutic strategy with which to improve ICB outcomes.

Sex-bias in CD8 T-cell stemness and exhaustion in cancer.

This commentary article highlights two recently published studies, which for the first time revealed the immunological underpinnings of sex-bias in cancer incidence and mortality. These studies showed that the androgen receptor restrains anti-tumour immunity in males by repressing cytotoxic genes in CD8 T cells.

Resident and migratory adipose immune cells control systemic metabolism and thermogenesis.

Glucose is a vital source of energy for all mammals. The balance between glucose uptake, metabolism and storage determines the energy status of an individual, and perturbations in this balance can lead to metabolic diseases. The maintenance of organismal glucose metabolism is a complex process that involves multiple tissues, including adipose tissue, which is an endocrine and energy storage organ that is critical for the regulation of systemic metabolism.

Early precursor T cells establish and propagate T cell exhaustion in chronic infection.

CD8 T cells responding to chronic infections or tumors acquire an 'exhausted' state associated with elevated expression of inhibitory receptors, including PD-1, and impaired cytokine production. Exhausted T cells are continuously replenished by T cells with precursor characteristics that self-renew and depend on the transcription factor TCF1; however, their developmental requirements are poorly understood. In the present study, we demonstrate that high antigen load promoted the differentiation of precursor T cells, which acquired hallmarks of exhaustion within days of infection, whereas early effector cells retained polyfunctional features.

Sex-specific adipose tissue imprinting of regulatory T cells.

Adipose tissue is an energy store and a dynamic endocrine organ. In particular, visceral adipose tissue (VAT) is critical for the regulation of systemic metabolism. Impaired VAT function-for example, in obesity-is associated with insulin resistance and type 2 diabetes.

Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis.

Differentiation and homeostasis of Foxp3 regulatory T (Treg) cells are strictly controlled by T-cell receptor (TCR) signals; however, molecular mechanisms that govern these processes are incompletely understood. Here we show that Bach2 is an important regulator of Treg cell differentiation and homeostasis downstream of TCR signaling. Bach2 prevents premature differentiation of fully suppressive effector Treg (eTreg) cells, limits IL-10 production and is required for the development of peripherally induced Treg (pTreg) cells in the gastrointestinal tract.

c-Maf-dependent T cell control of intestinal T17 cells and IgA establishes host-microbiota homeostasis.

Foxp3 regulatory T cells (T cells) are crucial for the maintenance of immune homeostasis both in lymphoid tissues and in non-lymphoid tissues. Here we demonstrate that the ability of intestinal T cells to constrain microbiota-dependent interleukin (IL)-17-producing helper T cell (T17 cell) and immunoglobulin A responses critically required expression of the transcription factor c-Maf. The terminal differentiation and function of several intestinal T cell populations, including RORγt T cells and follicular regulatory T cells, were c-Maf dependent.

Blimp1 Prevents Methylation of Foxp3 and Loss of Regulatory T Cell Identity at Sites of Inflammation.

Foxp3 regulatory T (Treg) cells restrict immune pathology in inflamed tissues; however, an inflammatory environment presents a threat to Treg cell identity and function. Here, we establish a transcriptional signature of central nervous system (CNS) Treg cells that accumulate during experimental autoimmune encephalitis (EAE) and identify a pathway that maintains Treg cell function and identity during severe inflammation. This pathway is dependent on the transcriptional regulator Blimp1, which prevents downregulation of Foxp3 expression and "toxic" gain-of-function of Treg cells in the inflamed CNS.

CCR2 enhances CD25 expression by FoxP3 regulatory T cells and regulates their abundance independently of chemotaxis and CCR2 myeloid cells.

A wide array of chemokine receptors, including CCR2, are known to control Treg migration. Here, we report that CCR2 regulates Tregs beyond chemotaxis. We found that CCR2 deficiency reduced CD25 expression by FoxP3 Treg cells.

Interleukin (IL)-33 and the IL-1 Family of Cytokines-Regulators of Inflammation and Tissue Homeostasis.

Cytokines play an integral role in shaping innate and adaptive immune responses. Members of the interleukin (IL)-1 family regulate a plethora of immune-cell-mediated processes, which include pathogen defense and tissue homeostasis. Notably, the IL-1 family cytokine IL-33 promotes adaptive and innate type 2 immune responses, confers viral protection and facilitates glucose metabolism and tissue repair.

The TNF Receptor Superfamily-NF-κB Axis Is Critical to Maintain Effector Regulatory T Cells in Lymphoid and Non-lymphoid Tissues.

After exiting the thymus, Foxp3 regulatory T (Treg) cells undergo further differentiation in the periphery, resulting in the generation of mature, fully suppressive effector (e)Treg cells in a process dependent on TCR signaling and the transcription factor IRF4. Here, we show that tumor necrosis factor receptor superfamily (TNFRSF) signaling plays a crucial role in the development and maintenance of eTreg cells. TNFRSF signaling activated the NF-κB transcription factor RelA, which was required to maintain eTreg cells in lymphoid and non-lymphoid tissues, including RORγt Treg cells in the small intestine.

A non-canonical function of Ezh2 preserves immune homeostasis.

Enhancer of zeste 2 (Ezh2) mainly methylates lysine 27 of histone-H3 (H3K27me3) as part of the polycomb repressive complex 2 (PRC2) together with Suz12 and Eed. However, Ezh2 can also modify non-histone substrates, although it is unclear whether this mechanism has a role during development. Here, we present evidence for a chromatin-independent role of Ezh2 during T-cell development and immune homeostasis.

The BCL-2 pro-survival protein A1 is dispensable for T cell homeostasis on viral infection.

The physiological role of the pro-survival BCL-2 family member A1 has been debated for a long time. Strong mRNA induction in T cells on T cell receptor (TCR)-engagement suggested a major role of A1 in the survival of activated T cells. However, the investigation of the physiological roles of A1 was complicated by the quadruplication of the A1 gene locus in mice, making A1 gene targeting very difficult.