Laurence E. Cheng
University of California, San Francisco
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Laurence E. Cheng.
Journal of Experimental Medicine | 2013
Ari B. Molofsky; Jesse C. Nussbaum; Hong-Erh Liang; Steven J. Van Dyken; Laurence E. Cheng; Alexander Mohapatra; Ajay Chawla; Richard M. Locksley
Innate lymphoid type 2 cells maintain eosinophils and alternatively activated macrophages in visceral fat via the production of IL-5 and IL-13.
Nature | 2013
Jesse C. Nussbaum; Steven J. Van Dyken; Jakob von Moltke; Laurence E. Cheng; Alexander Mohapatra; Ari B. Molofsky; Emily E. Thornton; Matthew F. Krummel; Ajay Chawla; Hong-Erh Liang; Richard M. Locksley
Eosinophils are specialized myeloid cells associated with allergy and helminth infections. Blood eosinophils demonstrate circadian cycling, as described over 80 years ago, and are abundant in the healthy gastrointestinal tract. Although a cytokine, interleukin (IL)-5, and chemokines such as eotaxins mediate eosinophil development and survival, and tissue recruitment, respectively, the processes underlying the basal regulation of these signals remain unknown. Here we show that serum IL-5 levels are maintained by long-lived type 2 innate lymphoid cells (ILC2) resident in peripheral tissues. ILC2 cells secrete IL-5 constitutively and are induced to co-express IL-13 during type 2 inflammation, resulting in localized eotaxin production and eosinophil accumulation. In the small intestine where eosinophils and eotaxin are constitutive, ILC2 cells co-express IL-5 and IL-13; this co-expression is enhanced after caloric intake. The circadian synchronizer vasoactive intestinal peptide also stimulates ILC2 cells through the VPAC2 receptor to release IL-5, linking eosinophil levels with metabolic cycling. Tissue ILC2 cells regulate basal eosinophilopoiesis and tissue eosinophil accumulation through constitutive and stimulated cytokine expression, and this dissociated regulation can be tuned by nutrient intake and central circadian rhythms.
Molecular and Cellular Biology | 1995
Francis Ka-Ming Chan; Zhang J; Laurence E. Cheng; Astar Winoto
The cell cycle in mammalian cells is regulated by a series of cyclins and cyclin-dependent kinases (CDKs). The G1/S checkpoint is mainly dictated by the kinase activities of the cyclin D-CDK4 and/or cyclin D-CDK6 complex and the cyclin E-CDK2 complex. These G1 kinases can in turn be regulated by cell cycle inhibitors, which may cause the cells to arrest at the G1 phase. In T-cell hybridomas, addition of anti-T-cell receptor antibody results not only in G1 arrest but also in apoptosis. In searching for a protein(s) which might interact with Nur77, an orphan steroid receptor required for activation-induced apoptosis of T-cell hybridomas, we have cloned a novel human and mouse CDK inhibitor, p19. The deduced p19 amino acid sequence consists of four ankyrin repeats with 48% identity to p16. The human p19 gene is located on chromosome 19p13, distinct from the positions of p18, p16, and p15. Its mRNA is expressed in all cell types examined. The p19 fusion protein can associate in vitro with CDK4 but not with CDK2, CDC2, or cyclin A, B, E, or D1 to D3. Addition of p19 protein can lead to inhibition of the in vitro kinase activity of cyclin D-CDK4 but not that of cyclin E-CDK2. In T-cell hybridoma DO11.10, p19 was found in association with CDK4 and CDK6 in vivo, although its association with Nur77 is not clear at this point. Thus, p19 is a novel CDK inhibitor which may play a role in the cell cycle regulation of T cells.
Molecular and Cellular Biology | 1995
John D. Woronicz; Andrea Lina; Barbara J. Calnan; Shannan Szychowski; Laurence E. Cheng; Andastar Winoto
T-cell receptor (TCR)-mediated apoptosis in immature thymocytes and T-cell hybridomas is calcium dependent and can be inhibited by cyclosporin A (CsA). Induction of the orphan steroid receptor Nur77 (NGFI-B) is required for activation-induced apoptosis. Here, we examined the regulation of Nur77 expression, in response to apoptotic TCR signals, which consists of kinase C and calcium pathways. We show that the major control of Nur77 induction is mediated by the calcium signaling pathway. In contrast, protein kinase C signals induce only a low level of Nur77 activity. Nur77 promoter activity parallels its protein levels. CsA decreases both Nur77 protein levels and promoter activity, and the kinetics of CsA inhibition of apoptosis correlates with a decrease in Nur77 protein levels. TCR signals and kinase C signals result in a similar level of Nur77 protein phosphorylation but mediate differential transactivation activity of Nur77. In addition, Nur77 promoter deletion analysis revealed two RSRF (related to serum-responsive factor) binding sites, which can confer calcium and CsA sensitivity on a heterologous promoter. Taken together, our data suggest that the levels of transcriptional induction of Nur77 play an important role during activation-induced apoptosis and that calcium signals regulate a novel CsA-sensitive nuclear factor required for Nur77 transcription in T cells.
Nature Immunology | 2011
Brandon M. Sullivan; Hong-Erh Liang; Jennifer K. Bando; Davina Wu; Laurence E. Cheng; James McKerrow; Christopher D.C. Allen; Richard M. Locksley
Contributions by basophils to allergic and helminth immunity remain incompletely defined. Using sensitive interleukin 4 (Il4) reporter alleles, we demonstrate here that basophil IL-4 production occurs by a CD4+ T cell–dependent process restricted to the peripheral tissues affected. We genetically marked and achieved specific deletion of basophils and found that basophils did not mediate T helper type 2 (TH2) priming in vivo. Two-photon imaging confirmed that basophils did not interact with antigen-specific T cells in lymph nodes but engaged in prolonged serial interactions with T cells in lung tissues. Although targeted deletion of IL-4 and IL-13 in either CD4+ T cells or basophils had a minimal effect on worm clearance, deletion from both lineages demonstrated a nonredundant role for basophil cytokines in primary helminth immunity.
Journal of Experimental Medicine | 2002
Claes Ohlen; Michael Kalos; Laurence E. Cheng; Aaron C. Shur; Doley J. Hong; Bryan D. Carson; Niels Kokot; Cara G. Lerner; Blythe D. Sather; Eric S. Huseby; Philip D. Greenberg
CD8+ T cell tolerance to self-proteins prevents autoimmunity but represents an obstacle to generating T cell responses to tumor-associated antigens. We have made a T cell receptor (TCR) transgenic mouse specific for a tumor antigen and crossed TCR-TG mice to transgenic mice expressing the tumor antigen in hepatocytes (gag-TG). TCRxgag mice showed no signs of autoimmunity despite persistence of high avidity transgenic CD8+ T cells in the periphery. Peripheral CD8+ T cells expressed phenotypic markers consistent with antigen encounter in vivo and had upregulated the antiapoptotic molecule Bcl-2. TCRxgag cells failed to proliferate in response to antigen but demonstrated cytolytic activity and the ability to produce interferon γ. This split tolerance was accompanied by inhibition of Ca2+ flux, ERK1/2, and Jun kinasephosphorylation, and a block in both interleukin 2 production and response to exogenous interleukin 2. The data suggest that proliferation and expression of specific effector functions characteristic of reactive cells are not necessarily linked in CD8+ T cell tolerance.
Proceedings of the National Academy of Sciences of the United States of America | 2002
Laurence E. Cheng; Claes Ohlen; Brad H. Nelson; Philip D. Greenberg
Multiple cytokines, including IL-2, can affect T cell proliferation and survival. However, IL-2 can lead to apoptosis as well as proliferation, making unclear whether IL-2 receptor (IL-2R) signals ultimately have a predominantly positive or negative effect. To address this issue, we examined the effect of enhancing IL-2R signals in CD8+ T cells after antigen stimulation by engineering a transgenic (Tg) mouse strain with CD8+ T cells capable of augmented, regulated, autocrine IL-2R signaling after target recognition by means of expression of a chimeric granulocyte-macrophage colony-stimulating factor (GM-CSF)/IL-2R. The Tg CD8+ T cells can bind the granulocyte-macrophage colony-stimulating GM-CSF produced by antigen stimulation, but the GM-CSF binding results in delivery of an IL-2R signal. After antigen stimulation in vivo, the Tg T cells demonstrated marked increases in the initial proliferative response and cell expansion and displayed continued increases in cell expansion after repeated antigen exposure. These data suggest that the predominant role of IL-2R signals delivered to responding CD8+ T cells is to set the size of the initial response to antigen by promoting T cell proliferation and survival and not cell death.
Clinical Immunology | 2009
Laurence E. Cheng; Bittoo Kanwar; Haig Tcheurekdjian; James P. Grenert; Mica Muskat; Melvin B. Heyman; Joseph M. McCune; Diane W. Wara
The NEMO syndrome is a primary immunodeficiency with immune and non-immune manifestations. The immune deficiency is heterogeneous showing defects in humoral, innate, and cell-mediated immunity. While the clinical aspects of the immunodeficiency are increasingly well understood, little is known about autoimmune manifestations in NEMO patients. We therefore sought to examine serologic markers of systemic inflammation and intestinal pathology in a kindred of patients with the NEMO syndrome. We observed persistent elevation of erythrocyte sedimentation rates in five patients, and two were symptomatic, with a chronic but atypical enterocolitis. Though pathologic lesions in these two patients were consistent with acute inflammation, sustained clinical improvement was only achieved with systemic and/or topical glucocorticoid therapy. Our data suggest that some patients with the NEMO syndrome exhibit persistent elevation of inflammatory markers similar to systemic autoimmune diseases and may subsequently develop an atypical enterocolitis.
Nature Immunology | 2002
Joseph N. Blattman; Laurence E. Cheng; Philip D. Greenberg
The resolution of an immune response was thought to coincide with the clearance of infection. However, the kinetics of CD8+ T cell decline may be programmed far before the antigen load lightens.
Journal of Immunology | 2002
Laurence E. Cheng; Philip D. Greenberg
CD8+ T cells respond to IL-2 produced both endogenously and by CD4+ Th during an antiviral response. However, IL-2R signals can potentially promote CD8+ T cell death as well as proliferation, making it unclear whether IL-2R signals provide a predominantly positive or negative effect upon CD8+ T cell responses to viral infection. To more precisely define the direct role of IL-2R signaling on CD8+ T cells during the response to a virus, we examined the effect of delivering augmented IL-2R signals selectively to CD8+ T cells responding to lymphocytic choriomeningitis virus infection. Although naive CD8+ T cells are competent to produce IL-2, CD8+ T cells lose this capacity upon differentiation into effector CD8+ T cells. However, effector CD8+ T cells do retain the capacity to produce GM-CSF upon Ag stimulation. Thus, to deliver enhanced autocrine IL-2R signals to CD8+ T cells, we established a transgenic mouse strain expressing a chimeric GM-CSF/IL-2R (GMIL2R). As GM-CSF production is Ag dependent, the GMIL2R delivers an augmented IL-2R signal exclusively to CD8+ T cells responding to Ag. Following lymphocytic choriomeningitis virus infection, GMIL2R transgenic mice exhibited an increase in both the peak CD8+ T cell response achieved and the size of the resulting memory pool established. Upon secondary viral challenge, the GMIL2R also enhanced the proliferative response of memory CD8+ T cells. Thus, our findings indicate that IL-2 delivery to responding CD8+ T cells is a limiting factor in both the acute and memory antiviral responses.