Faculty Bibliography
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133
Role Of Microbiota And Tcr Specificity In Th17 Mediated Airway Inflammation [Meeting Abstract]
ISI:000377582804328
ISSN: 1535-4970
CID: 2162082
Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2015:112(5):1256-1258.DOI: 10.1073/pnas.ss11205
PNAS Plus Significance Statements [Editorial]
ISI:000349087700026
ISSN: 0027-8424
CID: 2330672
Novel insights into Th17 mediated airway inflammation [Meeting Abstract]
ISI:000379404500080
ISSN: 1550-6606
CID: 2330772
STAT3 regulates iNKT cell development and function but is not required for NKT17 cell development [Meeting Abstract]
ISI:000379404502113
ISSN: 1550-6606
CID: 2330782
STAT3 Activation in Th17 and Th22 Cells Controls IL-22-Mediated Epithelial Host Defense during Infectious Colitis
The Citrobacter rodentium model mimics the pathogenesis of infectious colitis and requires sequential contributions from different immune cell populations, including innate lymphoid cells (ILCs) and CD4+ lymphocytes. In this study, we addressed the role of STAT3 activation in CD4+ cells during host defense in mice against C. rodentium. In mice with defective STAT3 in CD4+ cells (Stat3DeltaCD4), the course of infection was unchanged during the innate lymphoid cell-dependent early phase, but significantly altered during the lymphocyte-dependent later phase. Stat3DeltaCD4 mice exhibited intestinal epithelial barrier defects, including downregulation of antimicrobial peptides, increased systemic distribution of bacteria, and prolonged reduction in the overall burden of C. rodentium infection. Immunomonitoring of lamina propria cells revealed loss of virtually all IL-22-producing CD4+ lymphocytes, suggesting that STAT3 activation was required for IL-22 production not only in Th17 cells, but also in Th22 cells. Notably, the defective host defense against C. rodentium in Stat3CD4 mice could be fully restored by specific overexpression of IL-22 through a minicircle vector-based technology. Moreover, expression of a constitutive active STAT3 in CD4+ cells shaped strong intestinal epithelial barrier function in vitro and in vivo through IL-22, and it promoted protection from enteropathogenic bacteria. Thus, our work indicates a critical role of STAT3 activation in Th17 and Th22 cells for control of the IL-22-mediated host defense, and strategies expanding STAT3-activated CD4+ lymphocytes may be considered as future therapeutic options for improving intestinal barrier function in infectious colitis.
PMID: 25187663
ISSN: 0022-1767
CID: 1180922
Staphylococcal enterotoxins promote lymphoma-associated immune dysregulation by modulating benign and malignant T-cell interactions
Patients with cutaneous T-cell lymphoma (CTCL) are frequently colonized with Staphylococcus aureus (SA). Eradication of SA is, importantly, associated with significant clinical improvement suggesting that SA promotes the disease activity but the underlying mechanisms remain poorly characterized. Here we show that SA isolates from involved skin express staphylococcal enterotoxins (SEs) which induce cross-talk between malignant and benign T cells leading to Stat3-mediated IL-10 production by the malignant T cells. The SEs did not stimulate the malignant T cells directly. Instead, SEs triggered a cascade of events involving cell-cell and asymmetric cytokine interactions between malignant and benign T cells, which stimulated the malignant T cells to express high levels of IL-10. Much evidence supports that malignant activation of the Stat3/IL-10 axis plays a key role in driving the immune dysregulation and severe immunodeficiency that characteristically develops in CTCL patients. The present findings thereby establish a novel link between SEs and immune dysregulation in CTCL strengthening the rationale for antibiotic treatment of colonized patients with severe or progressive disease.
PMCID:4118485
PMID: 24957145
ISSN: 0006-4971
CID: 1050962
Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2014:111(25):E2622-9.DOI: 10.1073/pnas.1403278111
Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells
Antibody repertoires are known to be shaped by selection for antigen binding. Unexpectedly, we now show that selection also acts on a non-antigen-binding antibody region: the heavy-chain variable (VH)-encoded "elbow" between variable and constant domains. By sequencing 2.8 million recombined heavy-chain genes from immature and mature B-cell subsets in mice, we demonstrate a striking gradient in VH gene use as pre-B cells mature into follicular and then into marginal zone B cells. Cells whose antibodies use VH genes that encode a more flexible elbow are more likely to mature. This effect is distinct from, and exceeds in magnitude, previously described maturation-associated changes in heavy-chain complementarity determining region 3, a key antigen-binding region, which arise from junctional diversity rather than differential VH gene use. Thus, deep sequencing reveals a previously unidentified mode of B-cell selection.
PMCID:4078805
PMID: 24927543
ISSN: 0027-8424
CID: 1033972
Halofuginone-induced amino acid starvation regulates Stat3-dependent Th17 effector function and reduces established autoimmune inflammation
The IL-23 pathway is genetically linked to autoimmune disease in humans and is required for pathogenic Th17 cell function in mice. However, because IL-23R-expressing mature Th17 cells are rare and poorly defined in mice at steady-state, little is known about IL-23 signaling. In this study, we show that the endogenous CCR6(+) memory T cell compartment present in peripheral lymphoid organs of unmanipulated mice expresses Il23r ex vivo, displays marked proinflammatory responses to IL-23 stimulation in vitro, and is capable of transferring experimental autoimmune encephalomyelitis. The prolyl-tRNA synthetase inhibitor halofuginone blocks IL-23-induced Stat3 phosphorylation and IL-23-dependent proinflammatory cytokine expression in endogenous CCR6(+) Th17 cells via activation of the amino acid starvation response (AAR) pathway. In vivo, halofuginone shows therapeutic efficacy in experimental autoimmune encephalomyelitis, reducing both established disease progression and local Th17 cell effector function within the CNS. Mechanistically, AAR activation impairs Stat3 responses downstream of multiple cytokine receptors via selective, posttranscriptional suppression of Stat3 protein levels. Thus, our study reveals latent pathogenic functions of endogenous Th17 cells that are regulated by both IL-23 and AAR pathways and identifies a novel regulatory pathway targeting Stat3 that may underlie selective immune regulation by the AAR.
PMCID:3936195
PMID: 24489094
ISSN: 0022-1767
CID: 938112
STAT3 Activation in CD4+Lymphocytes Shapes Epithelial Host Defense During Infectious Colitis [Meeting Abstract]
ISI:000371236401327
ISSN: 1528-0012
CID: 2330722
STAT3 serine phosphorylation and HDAC inhibition in CTCL [Meeting Abstract]
Phosphorylation of signal transducer and activator of transcription 3 (STAT3) is essential for cell survival, proliferation and differentiation. STAT3 phosphorylation results from signaling by cytokines and growth factors, and constitutive STAT3 activity is characteristic of a number of human malignancies, including Cutaneous T Cell Lymphoma (CTCL). Furthermore, we now know that STAT3 is also required for the initiation and maintenance of the Th17 differentiation program. Th17 cells are a subset of CD4 T helper cells that have been implicated in chronic inflammatory conditions like rheumatoid arthritis and psoriasis. Mycosis fungoides (MF) and the leukemic variant of this disease, Sezary syndrome (SS), are the most frequently encountered forms of CTCL and in both of these diseases, the cell of origin - as far as the type of Teffector cell involved, has not been defined. Recent results from our laboratory and that of our colleagues have lead us to believe that Th17 cells may either be the cells of origin in CTCL or may act as critical mediators of chronic inflammation that creates a favorable environment for tumor growth in the context of this malignancy. In an effort to elucidate the role of STAT3 as a transforming factor in T cell malignancies, we generated a mouse model wherein T cell specific expression of a hyper-active STAT3 mutant protein (STAT3C) leads to the development of a lymphoproliferative disease that is highly reminiscent of CTCL. We are now taking advantage of this unique mouse model, patient biospecimens and carefully characterized CTCL cell lines to dissect the role of STAT3 signaling cascade in the malignant transformation and maintenance of CTCL. Most recently, our attention has been focused on understanding the mechanism of action of epigenetic therapy in the form of histone deacetylase inhibitors (HDACi), which is highly effective in the treatment of CTCL. We hypothesize that HDAC inhibitors affect the STAT3 mediated Th17 differentiation and thus have clinical efficacy in !
EMBASE:71263776
ISSN: 0006-4971
CID: 713082
