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Derya Unutmaz

Alka Khaitan, Max Kilberg, Adam Kravietz, Tiina Ilmet, Cihan Tastan, Mussa Mwamzuka, Fatma Marshed, Mengling Liu, Aabid Ahmed, William Borkowsky, Derya Unutmaz
Mucosal-associated invariant T cells (MAIT) are innate T cells restricted by major histocompatibility related molecule 1 (MR1) presenting riboflavin metabolite ligands derived from microbes. Specificity to riboflavin metabolites confers MAIT cells a broad array of host-protective activity against gram-negative and -positive bacteria, mycobacteria, and fungal pathogens. MAIT cells are present at low levels in the peripheral blood of neonates and gradually expand to relatively abundant levels during childhood...
2016: PloS One
Weijie Peng, Derya Unutmaz, Ibrahim T Ozbolat
Improving the ability to predict the efficacy and toxicity of drug candidates earlier in the drug discovery process will speed up the introduction of new drugs into clinics. 3D in vitro systems have significantly advanced the drug screening process as 3D tissue models can closely mimic native tissues and, in some cases, the physiological response to drugs. Among various in vitro systems, bioprinting is a highly promising technology possessing several advantages such as tailored microarchitecture, high-throughput capability, coculture ability, and low risk of cross-contamination...
September 2016: Trends in Biotechnology
Martin Vaeth, Miriam Eckstein, Patrick J Shaw, Lina Kozhaya, Jun Yang, Friederike Berberich-Siebelt, Robert Clancy, Derya Unutmaz, Stefan Feske
T follicular helper (Tfh) cells promote affinity maturation of B cells in germinal centers (GCs), whereas T follicular regulatory (Tfr) cells limit the GC reaction. Store-operated Ca(2+) entry (SOCE) through Ca(2+) release-activated Ca(2+) (CRAC) channels mediated by STIM and ORAI proteins is a fundamental signaling pathway in T lymphocytes. Conditional deletion of Stim1 and Stim2 genes in T cells abolished SOCE and strongly reduced antibody-mediated immune responses following viral infection caused by impaired differentiation and function of Tfh cells...
June 21, 2016: Immunity
Alka Khaitan, Adam Kravietz, Mussa Mwamzuka, Fatma Marshed, Tiina Ilmet, Swalehe Said, Aabid Ahmed, William Borkowsky, Derya Unutmaz
Regulatory T cells (Tregs) are functionally suppressive CD4 T cells, critical for establishing peripheral tolerance and controlling inflammatory responses. Previous reports of Tregs during chronic HIV disease have conflicting results with higher or lower levels compared with controls. Identifying true Tregs with suppressive activity proves challenging during HIV infection, as traditional Treg markers, CD25 and FOXP3, may transiently upregulate expression as a result of immune activation (IA). Helios is an Ikaros family transcription factor that marks natural Tregs with suppressive activity and does not upregulate expression after activation...
August 15, 2016: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Martin Vaeth, Isabelle Zee, Axel R Concepcion, Mate Maus, Patrick Shaw, Cynthia Portal-Celhay, Aleena Zahra, Lina Kozhaya, Carl Weidinger, Jennifer Philips, Derya Unutmaz, Stefan Feske
Store-operated Ca(2+) entry (SOCE) through Ca(2+) release-activated Ca(2+) (CRAC) channels is essential for immunity to infection. CRAC channels are formed by ORAI1 proteins in the plasma membrane and activated by stromal interaction molecule (STIM)1 and STIM2 in the endoplasmic reticulum. Mutations in ORAI1 and STIM1 genes that abolish SOCE cause severe immunodeficiency with recurrent infections due to impaired T cell function. SOCE has also been observed in cells of the innate immune system such as macrophages and dendritic cells (DCs) and may provide Ca(2+) signals required for their function...
August 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Scott VanCompernolle, Patricia B Smith, John H Bowie, Michael J Tyler, Derya Unutmaz, Louise A Rollins-Smith
The major mode of transmission of the human immunodeficiency virus (HIV) is by sexual intercourse. In the effort to halt the spread of HIV, one measure that holds great promise is the development of effective microbicides that can prevent transmission. Previously we showed that several amphibian antimicrobial peptides (AMPs) completely inhibit HIV infection of T cells while maintaining good viability of the T cell targets. These peptides also inhibited the transfer of HIV by dendritic cells (DCs) to T cells when added up to 8h after virus exposure...
September 2015: Peptides
Stephen A Rawlings, Francis Alonzo, Lina Kozhaya, Victor J Torres, Derya Unutmaz
Establishment of long-lived cellular reservoirs of HIV-1 represents a major therapeutic challenge to virus eradication. In this study, we utilized a human primary cell model of HIV-1 latency to evaluate the requirements for efficient virus reactivation from, and the selective elimination of, latently infected human T cells. Ectopic expression of BCL2 supported the replication and spread of R5-tropic HIV-1 in activated CD4(+) T cells. After IL-2 withdrawal, the HIV-1-infected T cells survived as resting cells for several months...
2015: PloS One
Ludovic Desvignes, Carl Weidinger, Patrick Shaw, Martin Vaeth, Theo Ribierre, Menghan Liu, Tawania Fergus, Lina Kozhaya, Lauren McVoy, Derya Unutmaz, Joel D Ernst, Stefan Feske
Chronic infections induce a complex immune response that controls pathogen replication, but also causes pathology due to sustained inflammation. Ca2+ influx mediates T cell function and immunity to infection, and patients with inherited mutations in the gene encoding the Ca2+ channel ORAI1 or its activator stromal interaction molecule 1 (STIM1) are immunodeficient and prone to chronic infection by various pathogens, including Mycobacterium tuberculosis (Mtb). Here, we demonstrate that STIM1 is required for T cell-mediated immune regulation during chronic Mtb infection...
June 2015: Journal of Clinical Investigation
Frances Mercer, Alka Khaitan, Lina Kozhaya, Judith A Aberg, Derya Unutmaz
A subset of human regulatory T cells (Tregs) secretes IL-17 and thus resembles Th17 effector cells. How IL-17(+) Tregs differentiate from naive precursors remains unclear. In this study, we show that IL-17-producing T cells can differentiate from CCR6(+) naive T cell precursors in the presence of IL-2, IL-1β, TGF-β, and IL-23. CCR6(+) naive T cells are present in adult peripheral and umbilical cord blood and in both conventional T naive and FOXP3(+) naive Treg subsets. IL-17(+) cells derived from CCR6(+) naive Tregs (referred to as IL-17(+) Tregs) express FOXP3 but not HELIOS, another Treg-associated transcription factor, and these cells display suppressor capacity and a surface phenotype resembling memory Tregs...
August 1, 2014: Journal of Immunology: Official Journal of the American Association of Immunologists
Radha Ramesh, Lina Kozhaya, Kelly McKevitt, Ivana M Djuretic, Thaddeus J Carlson, Maria A Quintero, Jacob L McCauley, Maria T Abreu, Derya Unutmaz, Mark S Sundrud
IL-17A-expressing CD4(+) T cells (Th17 cells) are generally regarded as key effectors of autoimmune inflammation. However, not all Th17 cells are pro-inflammatory. Pathogenic Th17 cells that induce autoimmunity in mice are distinguished from nonpathogenic Th17 cells by a unique transcriptional signature, including high Il23r expression, and these cells require Il23r for their inflammatory function. In contrast, defining features of human pro-inflammatory Th17 cells are unknown. We show that pro-inflammatory human Th17 cells are restricted to a subset of CCR6(+)CXCR3(hi)CCR4(lo)CCR10(-)CD161(+) cells that transiently express c-Kit and stably express P-glycoprotein (P-gp)/multi-drug resistance type 1 (MDR1)...
January 13, 2014: Journal of Experimental Medicine
Angela X Zhou, Aimee El Hed, Frances Mercer, Lina Kozhaya, Derya Unutmaz
A key modulator of immune homeostasis, TGFβ has an important role in the differentiation of regulatory T cells (Tregs) and IL-17-secreting T cells (Th17). How TGFβ regulates these functionally opposing T cell subsets is not well understood. We determined that an ADAM family metalloprotease called ADAM12 is specifically and highly expressed in both Tregs and CCR6+ Th17 cells. ADAM12 is induced in vitro upon differentiation of naïve T cells to Th17 cells or IL-17-secreting Tregs. Remarkably, silencing ADAM12 expression in CCR6+ memory T cells enhances the production of Th17 cytokines, similar to suppressing TGFβ signaling...
2013: PloS One
Tamara Reyes-Robles, Francis Alonzo, Lina Kozhaya, D Borden Lacy, Derya Unutmaz, Victor J Torres
The Staphylococcus aureus leukotoxin ED (LukED) is a pore-forming toxin required for the lethality associated with bacteremia in murine models. LukED targets the chemokine receptor CCR5 to kill T lymphocytes, macrophages, and dendritic cells. LukED also kills CCR5-deficient cells, like neutrophils, suggesting the existence of additional cellular receptors. Here, we identify the chemokine receptors CXCR1 and CXCR2 as the targets of LukED on neutrophils. The LukE subunit binds neutrophils in a specific and saturable manner, and this interaction is inhibited by CXCL8, the high-affinity endogenous ligand of CXCR1 and CXCR2...
October 16, 2013: Cell Host & Microbe
Justin P Edwards, Hodaka Fujii, Angela X Zhou, John Creemers, Derya Unutmaz, Ethan M Shevach
GARP/LRRC32 was defined as a marker of activated human regulatory T cells (Tregs) that is responsible for surface localization of latent TGF-β1. We find that GARP and latent TGF-β1 are also found on mouse Tregs activated via TCR stimulation; however, in contrast to human Tregs, GARP is also expressed at a low level on resting Tregs. The expression of GARP can be upregulated on mouse Tregs by IL-2 or IL-4 exposure in the absence of TCR signaling. GARP is expressed at a low level on Tregs within the thymus, and Treg precursors from the thymus concomitantly express GARP and Foxp3 upon exposure to IL-2...
June 1, 2013: Journal of Immunology: Official Journal of the American Association of Immunologists
Angela X Zhou, Lina Kozhaya, Hodaka Fujii, Derya Unutmaz
The role of surface-bound TGF-β on regulatory T cells (Tregs) and the mechanisms that mediate its functions are not well defined. We recently identified a cell-surface molecule called Glycoprotein A Repetitions Predominant (GARP), which is expressed specifically on activated Tregs and was found to bind latent TGF-β and mediate a portion of Treg suppressive activity in vitro. In this article, we address the role of GARP in regulating Treg and conventional T cell development and immune suppression in vivo using a transgenic mouse expressing GARP on all T cells...
May 15, 2013: Journal of Immunology: Official Journal of the American Association of Immunologists
Qi Wan, Lina Kozhaya, Keren Imberg, Frances Mercer, Shi Zhong, Michelle Krogsgaard, Derya Unutmaz
Activation of T cells through the engagement of the T cell receptors (TCRs) with specific peptide-MHC complexes on antigen presenting cells (APCs) is the major determinant for their proliferation, differentiation and display of effector functions. To assess the role of quantity and quality of peptide-MHC presentation in eliciting T cell activation and suppression functions, we genetically engineered human T cells with two TCRs that recognize HLA-A*0201-restricted peptides derived from either HIV or melanoma antigens...
2013: PloS One
Francis Alonzo, Lina Kozhaya, Stephen A Rawlings, Tamara Reyes-Robles, Ashley L DuMont, David G Myszka, Nathaniel R Landau, Derya Unutmaz, Victor J Torres
Pore-forming toxins are critical virulence factors for many bacterial pathogens and are central to Staphylococcus aureus-mediated killing of host cells. S. aureus encodes pore-forming bi-component leukotoxins that are toxic towards neutrophils, but also specifically target other immune cells. Despite decades since the first description of staphylococcal leukocidal activity, the host factors responsible for the selectivity of leukotoxins towards different immune cells remain unknown. Here we identify the human immunodeficiency virus (HIV) co-receptor CCR5 as a cellular determinant required for cytotoxic targeting of subsets of myeloid cells and T lymphocytes by the S...
January 3, 2013: Nature
Sylvia Adams, Lina Kozhaya, Frank Martiniuk, Tze-Chiang Meng, Luis Chiriboga, Leonard Liebes, Tsivia Hochman, Nicholas Shuman, Deborah Axelrod, James Speyer, Yelena Novik, Amy Tiersten, Judith D Goldberg, Silvia C Formenti, Nina Bhardwaj, Derya Unutmaz, Sandra Demaria
PURPOSE: Skin metastases of breast cancer remain a therapeutic challenge. Toll-like receptor 7 agonist imiquimod is an immune response modifier and can induce immune-mediated rejection of primary skin malignancies when topically applied. Here we tested the hypothesis that topical imiquimod stimulates local antitumor immunity and induces the regression of breast cancer skin metastases. EXPERIMENTAL DESIGN: A prospective clinical trial was designed to evaluate the local tumor response rate of breast cancer skin metastases treated with topical imiquimod, applied 5 d/wk for 8 weeks...
December 15, 2012: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Zandrea Ambrose, KyeongEun Lee, Jean Ndjomou, Hongzhan Xu, Ilker Oztop, James Matous, Taichiro Takemura, Derya Unutmaz, Alan Engelman, Stephen H Hughes, Vineet N KewalRamani
The antiviral factor CPSF6-358 interferes with the nuclear entry of human immunodeficiency virus type 1 (HIV-1). HIV-1 acquires resistance to CPSF6-358 through the N74D mutation of the capsid (CA), which alters its nuclear entry pathway. Here we show that compared to wild-type (WT) HIV-1, N74D HIV-1 is more sensitive to cyclosporine, has increased sensitivity to nevirapine, and is impaired in macrophage infection prior to reverse transcription. These phenotypes suggest a difference in the N74D reverse transcription complex that manifests early after infection and prior to interaction with the nuclear pore...
April 2012: Journal of Virology
Qi Wan, Lina Kozhaya, Aimee ElHed, Radha Ramesh, Thaddeus J Carlson, Ivana M Djuretic, Mark S Sundrud, Derya Unutmaz
Human memory T cells (T(M) cells) that produce IL-17 or IL-22 are currently defined as Th17 or Th22 cells, respectively. These T cell lineages are almost exclusively CCR6(+) and are important mediators of chronic inflammation and autoimmunity. However, little is known about the mechanisms controlling IL-17/IL-22 expression in memory Th17/Th22 subsets. We show that common γ chain (γc)-using cytokines, namely IL-2, IL-7, and IL-15, potently induce Th17-signature cytokine expression (Il17a, Il17f, Il22, and Il26) in CCR6(+), but not CCR6(-), T(M) cells, even in CCR6(+) cells lacking IL-17 expression ex vivo...
August 29, 2011: Journal of Experimental Medicine
Ashley L Dumont, Tyler K Nygaard, Robert L Watkins, Amanda Smith, Lina Kozhaya, Barry N Kreiswirth, Bo Shopsin, Derya Unutmaz, Jovanka M Voyich, Victor J Torres
Staphylococcus aureus is an important pathogen that continues to be a significant global health threat because of the prevalence of methicillin-resistant S. aureus strains (MRSA). The pathogenesis of this organism is partly attributed to the production of a large repertoire of cytotoxins that target and kill innate immune cells, which provide the first line of defence against S. aureus infection. Here we demonstrate that leukocidin A/B (LukAB) is required and sufficient for the ability of S. aureus, including MRSA, to kill human neutrophils, macrophages and dendritic cells...
February 2011: Molecular Microbiology
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