SUMMARY A unique population of Foxp3+CD4+ regulatory T (Treg) cells, with a distinct transcriptome and antigen-receptor repertoire, resides in visceral adipose tissue (VAT) of lean individuals. These cells regulate local inflammation and both local and systemic metabolic indices. Here we focus on expansion of the VAT Treg compartment in aging lean mice – assessing these cells’ phenotypic conversion from conventional CD4+ T cells, influx from lymphoid organs, and local population dynamics. Our findings establish that the VAT Treg compartment is seeded from thymocytes generated during the first weeks of life, and expands beyond 10 weeks of age due to indolent proliferation, of certain clones in particular, coupled with enhanced survival. Accumulation of VAT Tregs depends on antigen(s) presented by MHC class-II molecules and soluble mediators, notably interleukin(IL)-33. Addressing such factors therapeutically promises novel approaches for harnessing Tregs to stem the growing epidemic of obesity and consequent metabolic abnormalities.

IntroductionCD4 ϩ T cells are essential components of the adaptive immune system that regulate immune responses against foreign pathogens and tumors. Upon antigen recognition, naive CD4 ϩ T cells undergo activation and expansion, and then contract via programmed cell death. 1 Specific antigen challenges also induce CD4 ϩ T cells to differentiate into distinct Th cell lineages characterized by unique cytokine production profiles. 2 Among these lineages, Th1 cells, the differentiation of which is controlled by the master transcription factor T-bet, 3 are specialized for the clearance of intracellular infections and are implicated as the major effectors against tumors. 4 In addition, the conversion of effector T cells to Foxp3 ϩ inducible regulatory T cells (iTregs) is an important mechanism used to balance immune responses 5 that is exploited by tumors as a strategy for immune evasion. 6 Whereas the protein-based regulatory machinery that operates during the T-cell response has been vigorously explored, we have recently become aware of a novel and crucial element modulating T-cell function: miRNA. 7,8 miRNAs are 18-to 24-nucleotide noncoding RNAs that regulate gene expression by destabilizing target mRNAs, leading to mRNA degradation and/or translational repression. 9 Recent studies suggest that miRNA-mediated gene regulation represents a fundamental layer of posttranscriptional regulatory programs in metazoan genomes. 10 Global disruption of miRNAs caused by defective biogenesis had profound effects on the development of B cells, 11 Th1/Th2 differentiation, 12,13 and Treg function. 14,15 In addition to these demonstrations of the importance of miRNA biogenesis in general, accumulating evidence shows that many specific miRNAs are differentially regulated in hematopoietic lineages and play important roles in controlling the development and function of immune cells. 7,8,[16][17][18] One such regulator is the miR-17-92 cluster.This cluster of miRNAs is encoded by a polycistronic miRNA gene and generates a single transcript that yields 6 individual mature miRNAs. These miRNAs are categorized into 3 families based on sequence homology: the miR-17 family (miR-17, miR-20, and miR-18a), the miR-19 family (miR-19a and miR-19b), and the miR-25 family (miR-92a; supplemental Figure 1A, available on the Blood Web site; see the Supplemental Materials link at the top of the online article). miR-17-92 is well recognized as an "onco-miR" because of its genomic amplification in certain tumor tissues and its potent acceleration of c-My-induced B-cell lymphoma. 19 Genetic ablation has clearly established the critical roles of miR-17-92 in embryonic development. 20 In immune cells, miR-17-92 plays an integral part in the development of myeloid cells and B cells. 20,21 Mice with germline deletion of miR-17-92 exhibit a severe defect in adult B-cell development with an augmentation of apoptosis in the pro-B-cell fraction and consequently a blockade at the pro-B to pre-B transition. 20 In addition, transgenic mice overexpressing the miR-...

The tumour stroma is an active participant during cancer progression. Stromal cells promote tumour progression and metastasis through multiple mechanisms including enhancing tumour invasiveness and angiogenesis, and suppressing immune surveillance. We report here that miR-126/miR-126*, a microRNA pair derived from a single precursor, independently suppress the sequential recruitment of mesenchymal stem cells and inflammatory monocytes into the tumour stroma to inhibit lung metastasis by breast tumour cells in a mouse xenograft model. miR-126/miR-126* directly inhibit stromal cell-derived factor-1 alpha (Sdf-1α) expression, and indirectly suppress the expression of chemokine (C–C motif) ligand 2 (Ccl2) by cancer cells in an Sdf-1α-dependent manner. miR-126/miR-126* expression is downregulated in cancer cells by promoter methylation of their host gene Egfl7. These findings determine how this microRNA pair alters the composition of the primary tumour microenvironment to favour breast cancer metastasis, and demonstrate a correlation between miR-126/126* downregulation and poor metastasis-free survival of breast cancer patients.

SUMMARY Visceral adipose tissue (VAT) hosts a population of regulatory T (Treg) cells, with a unique phenotype, that controls local and systemic inflammation and metabolism. Generation of a T-cell receptor transgenic mouse line, wherein VAT Tregs are highly enriched, facilitated study of their provenance, dependencies, and activities. We definitively established a role for T-cell receptor specificity, uncovered an unexpected function for the primordial Treg transcription-factor, Foxp3, evidenced a cell-intrinsic role for interleukin-33 receptor, and ordered these dependencies within a coherent scenario. Genesis of the VAT-Treg phenotype entailed a priming step in the spleen, permitting them to exit the lymphoid organs and surveil nonlymphoid tissues, and a final diversification process within VAT, in response to microenvironmental cues. Understanding the principles of tissue-Treg biology is a prerequisite for precision-targeting strategies.