1. Long-Range Transcriptional Control of the Il2 Gene by an Intergenic Enhancer.

    Molecular and Cellular Biology 35(22):3880 (2015) PMID 26351138 PMCID PMC4609740

    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...
  2. DNA binding by FOXP3 domain-swapped dimer suggests mechanisms of long-range chromosomal interactions.

    Nucleic Acids Research 43(2):1268 (2015) PMID 25567984 PMCID PMC4333414

    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...
  3. Regulatory T cells suppress CD4+ T cells through NFAT-dependent transcriptional mechanisms.

    EMBO Reports 15(9):991 (2014) PMID 25074018 PMCID PMC4198043

    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...
  4. 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) PMID 24878043 PMCID PMC4121035

    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...
  5. Ikaros imposes a barrier to CD8+ T cell differentiation by restricting autocrine IL-2 production.

    Journal of Immunology 192(11):5118 (2014) PMID 24778448 PMCID PMC4042307

    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. ...
  6. 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) PMID 24337390

    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...
  7. New roles for cyclin-dependent kinases in T cell biology: linking cell division and differentiation.

    Nature Reviews: Immunology 14(4):261 (2014) PMID 24603166

    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...
  8. Regulation of T cell differentiation and alloimmunity by the cyclin-dependent kinase inhibitor p18ink4c.

    PLoS ONE 9(3):e91587 (2014) PMID 24614758 PMCID PMC3948896

    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...
  9. 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) PMID 25469308 PMCID PMC4250976

    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...
  10. Mbd2 promotes foxp3 demethylation and T-regulatory-cell function.

    Molecular and Cellular Biology 33(20):4106 (2013) PMID 23979593 PMCID PMC3811679

    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...
  11. Foxp3 protein stability is regulated by cyclin-dependent kinase 2.

    Journal of Biological Chemistry 288(34):24494 (2013) PMID 23853094 PMCID PMC3750148

    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 ...
  12. Cyclin-dependent kinase 2 controls peripheral immune tolerance.

    Journal of Immunology 189(12):5659 (2012) PMID 23136201 PMCID PMC3518671

    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...
  13. Conserved intergenic elements and DNA methylation cooperate to regulate transcription at the il17 locus.

    Journal of Biological Chemistry 287(30):25049 (2012) PMID 22665476 PMCID PMC3408191

    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...
  14. De novo DNA methylation is required to restrict T helper lineage plasticity.

    Journal of Biological Chemistry 287(27):22900 (2012) PMID 22584578 PMCID PMC3391093

    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 ...
  15. Structural and biological features of FOXP3 dimerization relevant to regulatory T cell function.

    Cell Reports 1(6):665 (2012) PMID 22813742 PMCID PMC3401381

    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...
  16. Ikaros silences T-bet expression and interferon-gamma production during T helper 2 differentiation.

    Journal of Biological Chemistry 285(4):2545 (2010) PMID 19923223 PMCID PMC2807311

    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...
  17. Mutiny on the Boun-T: controlling dangerous T cells through anergy.

    Discovery medicine 9(44):16 (2010) PMID 20102680

    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...
  18. FOXP3 inhibits activation-induced NFAT2 expression in T cells thereby limiting effector cytokine expression.

    Journal of Immunology 183(2):907 (2009) PMID 19564342 PMCID PMC2778477

    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...
  19. New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting.

    Journal of Immunology 182(12):7331 (2009) PMID 19494254

    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...
  20. Foxp3 processing by proprotein convertases and control of regulatory T cell function.

    Journal of Biological Chemistry 284(9):5709 (2009) PMID 19117830 PMCID PMC2645825

    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 ...