Long-Range Transcriptional Control of the Il2 Gene by an Intergenic Enhancer.
Molecular and Cellular Biology 35(22):3880 (2015)
Interleukin-2 (IL-2) is a potent cytokine with roles in both immunity and tolerance. Genetic studies in humans and mice demonstrate a role for Il2 in autoimmune disease susceptibility, and for decades the proximal Il2 upstream regulatory region has served as a paradigm of tissue-specific, induci...
DNA binding by FOXP3 domain-swapped dimer suggests mechanisms of long-range chromosomal interactions.
Nucleic Acids Research 43(2):1268 (2015)
FOXP3 is a lineage-specific transcription factor that is required for regulatory T cell development and function. In this study, we determined the crystal structure of the FOXP3 forkhead domain bound to DNA. The structure reveals that FOXP3 can form a stable domain-swapped dimer to bridge DNA in...
Regulatory T cells suppress CD4+ T cells through NFAT-dependent transcriptional mechanisms.
EMBO Reports 15(9):991 (2014)
Regulatory T cells (Tregs) control autoreactive T cells by inhibiting activation-induced proliferation and cytokine expression. The molecular mechanisms responsible for the inactivation of effector T cells by Tregs remain yet to be fully characterized. We report that T-helper cells stimulated in...
Genome-wide analyses of ChIP-Seq derived FOXA2 DNA occupancy in liver points to genetic networks underpinning multiple complex traits.
Journal of Clinical Endocrinology & Metabolism 99(8):E1580 (2014)
Forkhead Box A2 (FOXA2) exerts an influence on glucose homeostasis via activity in the liver. In addition, a key genome-wide association study (GWAS) recently demonstrated that genetic variation, namely rs6048205, at the FOXA2 locus is robustly associated with fasting glucose levels. Our hypothe...
Ikaros imposes a barrier to CD8+ T cell differentiation by restricting autocrine IL-2 production.
Journal of Immunology 192(11):5118 (2014)
Naive CD4(+) T cells require signals from the TCR and CD28 to produce IL-2, expand, and differentiate. However, these same signals are not sufficient to induce autocrine IL-2 production by naive CD8(+) T cells, which require cytokines provided by other cell types to drive their differentiation. ...
A ChIP-seq-defined genome-wide map of MEF2C binding reveals inflammatory pathways associated with its role in bone density determination.
Calcified Tissue International 94(4):396 (2014)
Genome-wide association studies (GWAS) have demonstrated that genetic variation at the MADS box transcription enhancer factor 2, polypeptide C (MEF2C) locus is robustly associated with bone mineral density, primarily at the femoral neck. MEF2C is a transcription factor known to operate via the W...
New roles for cyclin-dependent kinases in T cell biology: linking cell division and differentiation.
Nature Reviews: Immunology 14(4):261 (2014)
The proliferation of a few antigen-reactive lymphocytes into a large population of effector cells is a fundamental property of adaptive immunity. The cell division that fuels this process is driven by signals from antigen, co-stimulatory molecules and growth factor receptors, and is controlled b...
Regulation of T cell differentiation and alloimmunity by the cyclin-dependent kinase inhibitor p18ink4c.
PLoS ONE 9(3):e91587 (2014)
Cellular proliferation in response to mitogenic stimuli is negatively regulated by the Cip/Kip and the Ink4 families of cyclin-dependent kinase (CDK) inhibitors. Several of these proteins are elevated in anergic T cells, suggesting a potential role in the induction or maintenance of tolerance. O...
Two novel type 2 diabetes loci revealed through integration of TCF7L2 DNA occupancy and SNP association data.
BMJ Open Diabetes Research & Care 2(1):e000052 (2014)
The transcription factor 7-like 2 (TCF7L2) locus is strongly implicated in the pathogenesis of type 2 diabetes (T2D). We previously mapped the genomic regions bound by TCF7L2 using ChIP (chromatin immunoprecipitation)-seq in the colorectal carcinoma cell line, HCT116, revealing an unexpected hig...
Mbd2 promotes foxp3 demethylation and T-regulatory-cell function.
Molecular and Cellular Biology 33(20):4106 (2013)
Use of Foxp3-positive (Foxp3(+)) T-regulatory (Treg) cells as potential cellular therapy in patients with autoimmunity, or post-stem cell or -organ transplantation, requires a sound understanding of the transcriptional regulation of Foxp3. Conserved CpG dinucleotides in the Treg-specific demethy...
Foxp3 protein stability is regulated by cyclin-dependent kinase 2.
Journal of Biological Chemistry 288(34):24494 (2013)
Foxp3 is a transcription factor required for the development of regulatory T cells (Treg). Mice and humans with a loss of Foxp3 function suffer from uncontrolled autoimmunity and inflammatory disease. Expression of Foxp3 is necessary for the anti-inflammatory capacity of Treg, but whether Foxp3 ...
Cyclin-dependent kinase 2 controls peripheral immune tolerance.
Journal of Immunology 189(12):5659 (2012)
Adaptive immunity requires signals from both the TCR and the costimulatory molecule CD28. These receptors activate multiple signaling pathways, including the cyclin-dependent kinase (CDK) cascade, and antigenic signals in the absence of costimulation result in a tolerant state that is enforced b...
Conserved intergenic elements and DNA methylation cooperate to regulate transcription at the il17 locus.
Journal of Biological Chemistry 287(30):25049 (2012)
Naive CD4(+) T cells can differentiate into distinct lineages with unique immune functions. The cytokines TGFβ and IL-6 promote the development of Th17 cells that produce IL-17, an inflammatory cytokine not expressed by other T helper lineages. To further understand how IL-17 production is contr...
De novo DNA methylation is required to restrict T helper lineage plasticity.
Journal of Biological Chemistry 287(27):22900 (2012)
Naïve CD4+ T cells are highly plastic and can differentiate into discrete lineages with unique functions during an immune response. Once differentiated, helper T cells maintain a stable transcriptional memory of their initial lineage choice and resist redifferentiation. During embryogenesis, de ...
Structural and biological features of FOXP3 dimerization relevant to regulatory T cell function.
Cell Reports 1(6):665 (2012)
FOXP3 is a key transcription factor for regulatory T cell function. We report the crystal structure of the FOXP3 coiled-coil domain, through which a loose or transient dimeric association is formed and modulated, accounting for the activity variations introduced by disease-causing mutations or p...
Ikaros silences T-bet expression and interferon-gamma production during T helper 2 differentiation.
Journal of Biological Chemistry 285(4):2545 (2010)
CD4+ T cells can be instructed by nonantigen-specific signals to differentiate into functionally distinct lineages with mutually exclusive patterns of cytokine production. The molecular events that drive interferon-gamma (IFN gamma) production during Th1 development are well understood, but mech...
Mutiny on the Boun-T: controlling dangerous T cells through anergy.
Discovery medicine 9(44):16 (2010)
In this review, I outline a current view of how T lymphocytes use extracellular signals to decide between activation and tolerance, and how the tolerant state is established and maintained at the molecular level. This decision is made by a series of intracellular proteins that actively oppose th...
FOXP3 inhibits activation-induced NFAT2 expression in T cells thereby limiting effector cytokine expression.
Journal of Immunology 183(2):907 (2009)
The forkhead DNA-binding protein FOXP3 is critical for the development and suppressive function of CD4(+)CD25(+) regulatory T cells (T(REG)), which play a key role in maintaining self-tolerance. Functionally, FOXP3 is capable of repressing transcription of cytokine genes regulated by NFAT. Vario...
New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting.
Journal of Immunology 182(12):7331 (2009)
The vertebrate immune system has evolved to deal with invasive pathogens, but this adaptation comes at the expense of immunopathology. Among a number of mechanisms that coevolved to control adaptive immunity is anergy, the functional inactivation of T lymphocytes that respond to Ag in the absenc...
Foxp3 processing by proprotein convertases and control of regulatory T cell function.
Journal of Biological Chemistry 284(9):5709 (2009)
Foxp3 is a 47-kDa transcription factor central to regulatory T cell (Treg) function. The importance of Foxp3(+) Tregs in controlling self-reactive T cells and preventing autoimmunity is well established. Our analysis of Foxp3 expression in natural Tregs led to identification of a shorter 41-kDa ...