Publications by authors named "Steven D Levin"

24 Publications

  • Page 1 of 1

ICOSL plasmacytoid dendritic cells as inducer of graft-versus-host disease, responsive to a dual ICOS/CD28 antagonist.

Sci Transl Med 2020 10;12(564)

Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic hematopoietic cell transplantation (HCT). CD146 and CCR5 are proteins that mark activated T helper 17 (Th17) cells. The Th17 cell phenotype is promoted by the interaction of the receptor ICOS on T cells with ICOS ligand (ICOSL) on dendritic cells (DCs). We performed multiparametric flow cytometry in a cohort of 156 HCT recipients and conducted experiments with aGVHD murine models to understand the role of ICOSL DCs. We observed an increased frequency of ICOSL plasmacytoid DCs, correlating with CD146CCR5 T cell frequencies, in the 64 HCT recipients with gastrointestinal aGVHD. In murine models, donor bone marrow cells from ICOSL-deficient mice compared to those from wild-type mice reduced aGVHD-related mortality. Reduced aGVHD resulted from lower intestinal infiltration of pDCs and pathogenic Th17 cells. We transplanted activated human ICOSL pDCs along with human peripheral blood mononuclear cells into immunocompromised mice and observed infiltration of intestinal CD146CCR5 T cells. We found that prophylactic administration of a dual human ICOS/CD28 antagonist (ALPN-101) prevented aGVHD in this model better than did the clinically approved belatacept (CTLA-4-Fc), which binds CD80 (B7-1) and CD86 (B7-2) and interferes with the CD28 T cell costimulatory pathway. When started at onset of aGVHD signs, ALPN-101 treatment alleviated symptoms of ongoing aGVHD and improved survival while preserving antitumoral cytotoxicity. Our data identified ICOSL-pDCs as an aGVHD biomarker and suggest that coinhibition of the ICOSL/ICOS and B7/CD28 axes with one biologic drug may represent a therapeutic opportunity to prevent or treat aGVHD.
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http://dx.doi.org/10.1126/scitranslmed.aay4799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811191PMC
October 2020

Novel Immunomodulatory Proteins Generated via Directed Evolution of Variant IgSF Domains.

Front Immunol 2019 21;10:3086. Epub 2020 Jan 21.

Alpine Immune Sciences Inc., Seattle, WA, United States.

Immunoglobulin superfamily member (IgSF) proteins play a significant role in regulating immune responses with surface expression on all immune cell subsets, making the IgSF an attractive family of proteins for therapeutic targeting in human diseases. We have developed a directed evolution platform capable of engineering IgSF domains to increase affinities for cognate ligands and/or introduce binding to non-cognate ligands. Using this scientific platform, ICOSL domains have been derived with enhanced binding to ICOS and with additional high-affinity binding to the non-cognate receptor, CD28. Fc-fusion proteins containing these engineered ICOSL domains significantly attenuate T cell activation and and can inhibit development of inflammatory diseases in mouse models. We also present evidence that engineered ICOSL domains can be formatted to selectively provide costimulatory signals to augment T cell responses. Our scientific platform thus provides a system for developing therapeutic protein candidates with selective biological impact for treatments of a wide array of human disorders including cancer and autoimmune/inflammatory diseases.
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http://dx.doi.org/10.3389/fimmu.2019.03086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985287PMC
November 2020

Biomechanical strain characteristics of soft tissue biceps tenodesis and bony tenodesis.

J Orthop Sci 2013 Sep 27;18(5):699-704. Epub 2013 Jul 27.

Department of Orthopaedic Surgery, Northshore University Health System, 1000 Central Street, Suite 880, Evanston, IL, 60201, USA.

Background: Biomechanical analysis of biceps tenodesis procedures has historically focused on load to failure models. Minimal data exists for the analysis of biomechanical strain properties of the biceps tendon in a sub-failure, physiologic cadaver model.

Hypothesis: Tendon strain characteristics are different between bony and soft tissue tenodesis surgery, and the soft tissue tenodesis procedure reproduces a strain pattern more similar to the native biceps tendon.

Methods: Eight fresh frozen cadaver upper extremities were mounted onto a custom device that controls shoulder abduction and rotation. Strain on the tendon was measured using a differential variable reluctance transducer as the arm was moved through cycles of abduction and external rotation. Each arm was mounted once, and all 3 testing procedures were performed on each of the 8 specimens. Statistical analysis was completed using ANOVA, followed by multiple comparisons with Bonferroni correction.

Results: The bony tenodesis model placed higher strain on the biceps tendon than the soft tissue tenodesis (p = 0.025). Also, the bony tenodesis model increased the strain on the biceps tendon when compared to the native tendon (p = 0.031). In contrast, the soft tissue tenodesis did not significantly alter strain when compared to the native tendon (p = 0.089).

Conclusion: The soft tissue tenodesis procedure better maintained the native strain environment when compared to the bony tenodesis using an interference screw. Due to this closer approximation of native biceps tendon biomechanics, the soft tissue procedure may be more preferable clinically than the bony tenodesis.

Level Of Evidence: 1, Controlled Laboratory Study.
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http://dx.doi.org/10.1007/s00776-013-0429-7DOI Listing
September 2013

Neer Award 2012: cerebral oxygenation in the beach chair position: a prospective study on the effect of general anesthesia compared with regional anesthesia and sedation.

J Shoulder Elbow Surg 2013 Oct 6;22(10):1325-31. Epub 2013 Apr 6.

Department of Orthopaedic Surgery, NorthShore University HealthSystem, University of Chicago, Evanston, IL, USA. Electronic address:

Background: Devastating neurologic ischemic episodes, such as stroke and deafness, have occurred in patients undergoing shoulder surgery in the beach chair position. We hypothesized that awake patients would be able to avoid significant cerebral deoxygenation events (CDEs) compared with anesthetized patients when procedures were performed in the beach chair position.

Materials And Methods: Sixty patients underwent elective shoulder surgery in the beach chair position. Thirty patients underwent an interscalene block and monitored sedation (awake group); 30 patients underwent general anesthesia (asleep group). Cerebral oxygenation saturation (Scto2) was measured during the procedure. Scto2 values below critical thresholds were defined as CDEs and treated.

Results: Baseline mean arterial pressure and Scto2 values were lower in the asleep group during the operation (P < .0001). A higher incidence of CDEs was seen in the asleep group (56.7% vs 0% awake group), and more CDEs were seen per patient (2.97 in asleep vs 0 awake, P < .0001). Scto2 below a threshold value of 55% was seen in 23.3% in the asleep group vs 3.3% in the awake group. A total of 89 combined desaturation events were documented in the asleep vs 1 in the awake group (P < .0001).

Conclusions: Patients in the beach chair position treated with regional anesthesia and sedation had almost no cerebral desaturation events, unlike patients who had general anesthesia. Avoidance of general anesthesia in the beach chair position may reduce the risk of ischemic neurologic injury.
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http://dx.doi.org/10.1016/j.jse.2013.01.035DOI Listing
October 2013

IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens.

Nat Immunol 2011 Oct 12;12(12):1151-8. Epub 2011 Oct 12.

The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Interleukin 17 receptor E (IL-17RE) is an orphan receptor of the IL-17 receptor family. Here we show that IL-17RE is a receptor specific to IL-17C and has an essential role in host mucosal defense against infection. IL-17C activated downstream signaling through IL-17RE-IL-17RA complex for the induction of genes encoding antibacterial peptides as well as proinflammatory molecules. IL-17C was upregulated in colon epithelial cells during infection with Citrobacter rodentium and acted in synergy with IL-22 to induce the expression of antibacterial peptides in colon epithelial cells. Loss of IL-17C-mediated signaling in IL-17RE-deficient mice led to lower expression of genes encoding antibacterial molecules, greater bacterial burden and early mortality during infection. Together our data identify IL-17RE as a receptor of IL-17C that regulates early innate immunity to intestinal pathogens.
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http://dx.doi.org/10.1038/ni.2155DOI Listing
October 2011

A role for IL-27 in limiting T regulatory cell populations.

J Immunol 2011 Jul 27;187(1):266-73. Epub 2011 May 27.

Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104, USA.

IL-27 is a cytokine that regulates Th function during autoimmune and pathogen-induced immune responses. Although previous studies have shown that regulatory T cells (Tregs) express the IL-27R, and that IL-27 inhibits forkhead box P3 upregulation in vitro, little is known about how IL-27 influences Tregs in vivo. The studies presented in this article show that mice that overexpress IL-27 had decreased Treg frequencies and developed spontaneous inflammation. Although IL-27 did not cause mature Tregs to downregulate forkhead box P3, transgenic overexpression in vivo limited the size of a differentiating Treg population in a bone marrow chimera model, which correlated with reduced production of IL-2, a vital cytokine for Treg maintenance. These data identify an indirect role for IL-27 in shaping the Treg pool.
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http://dx.doi.org/10.4049/jimmunol.1004182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119737PMC
July 2011

Vstm3 is a member of the CD28 family and an important modulator of T-cell function.

Eur J Immunol 2011 Apr 18;41(4):902-15. Epub 2011 Mar 18.

Department of Immunology, ZymoGenetics, Inc., Seattle, WA, USA.

Members of the CD28 family play important roles in regulating T-cell functions and share a common gene structure profile. We have identified VSTM3 as a protein whose gene structure matches that of the other CD28 family members. This protein (also known as TIGIT and WUCAM) has been previously shown to affect immune responses and is expressed on NK cells, activated and memory T cells, and Tregs. The nectin-family proteins CD155 and CD112 serve as counter-structures for VSTM3, and CD155 and CD112 also bind to the activating receptor CD226 on T cells and NK cells. Hence, this group of interacting proteins forms a network of molecules similar to the well-characterized CD28-CTLA-4-CD80-CD86 network. In the same way that soluble CTLA-4 can be used to block T-cell responses, we show that soluble Vstm3 attenuates T-cell responses in vitro and in vivo. Moreover, animals deficient in Vstm3 are more sensitive to autoimmune challenges indicating that this new member of the CD28 family is an important regulator of T-cell responses.
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http://dx.doi.org/10.1002/eji.201041136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733993PMC
April 2011

Cutting edge: TIGIT has T cell-intrinsic inhibitory functions.

J Immunol 2011 Feb 3;186(3):1338-42. Epub 2011 Jan 3.

Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Costimulatory molecules regulate the functional outcome of T cell activation, and disturbance of the balance between activating and inhibitory signals results in increased susceptibility to infection or the induction of autoimmunity. Similar to the well-characterized CD28/CTLA-4 costimulatory pathway, a newly emerging pathway consisting of CD226 and T cell Ig and ITIM domain (TIGIT) has been associated with susceptibility to multiple autoimmune diseases. In this study, we examined the role of the putative coinhibitory molecule TIGIT and show that loss of TIGIT in mice results in hyperproliferative T cell responses and increased susceptibility to autoimmunity. TIGIT is thought to indirectly inhibit T cell responses by the induction of tolerogenic dendritic cells. By generating an agonistic anti-TIGIT Ab, we demonstrate that TIGIT can inhibit T cell responses directly independent of APCs. Microarray analysis of T cells stimulated with agonistic anti-TIGIT Ab revealed that TIGIT can act directly on T cells by attenuating TCR-driven activation signals.
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http://dx.doi.org/10.4049/jimmunol.1003081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128994PMC
February 2011

Lck regulates IL-10 expression in memory-like Th1 cells.

Eur J Immunol 2010 Nov 27;40(11):3210-9. Epub 2010 Oct 27.

Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

The Src family kinase Lck is thought to facilitate Th2 differentiation; however, its role in Th1 cells has not been well explored. Using mice that lack Lck in mature T cells, we find that lck(-/-) Th1 skewed cells have normal expression of T-bet and produce IFN-γ at WT levels. However, there is a 3-fold increase in IL-10 producing cells in the mutant cultures. These cells do not have elevated levels of IL-4, GATA3, IL-17 or Foxp3, indicating that they are not Th2, Th17, or Foxp3(+) T regulatory cells (Treg). Nor do these cells behave in a similar manner as the type 1 Treg. Most of the IL-10 in the lck(-/-) Th1 cultures is derived from the memory/activated subset, as the cytokine profile from Th1 cultures established from purified CD62L(+) (naïve) cells are similar to WT cells. Furthermore, this IL-10 expression appears to be dependent on IL-12 and correlates with elevated c-Maf. These data highlight a previously unappreciated role for Lck in regulating IL-10 in Th1 cells.
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http://dx.doi.org/10.1002/eji.201040699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517127PMC
November 2010

A role for IL-27p28 as an antagonist of gp130-mediated signaling.

Nat Immunol 2010 Dec 7;11(12):1119-26. Epub 2010 Nov 7.

University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA.

The heterodimeric cytokine interleukin 27 (IL-27) signals through the IL-27Rα subunit of its receptor, combined with gp130, a common receptor chain used by several cytokines, including IL-6. Notably, the IL-27 subunits p28 (IL-27p28) and EBI3 are not always expressed together, which suggests that they may have unique functions. Here we show that IL-27p28, independently of EBI3, antagonized cytokine signaling through gp130 and IL-6-mediated production of IL-17 and IL-10. Similarly, the ability to generate antibody responses was dependent on the activity of gp130-signaling cytokines. Mice transgenic for expression of IL-27p28 showed a substantial defect in the formation of germinal centers and antibody production. Thus, IL-27p28, as a natural antagonist of gp130-mediated signaling, may be useful as a therapeutic for managing inflammation mediated by cytokines that signal through gp130.
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http://dx.doi.org/10.1038/ni.1957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059498PMC
December 2010

Strain effects of placing an arthroscopic portal through the subscapularis tendon.

J Shoulder Elbow Surg 2011 Jan 4;20(1):33-8. Epub 2010 Nov 4.

Southern California Permanente Medical Group, San Diego, CA, USA.

Hypothesis: The biomechanical effects of placing a portal through the subscapularis tendon have not been studied. Our hypothesis is that placing a portal through the subscapularis tendon will affect the strain properties of the tendon.

Materials And Methods: Eight shoulders from deceased donors were dissected to expose the subscapularis musculotendinous unit. The subscapularis muscle was isolated, the arm was locked at neutral (0° abduction, 0° flexion/extension, 0° external rotation/internal rotation), and 3 cables were sutured to the subscapularis musculotendinous junction. Each cable was connected to a static weight. Three differential variable reluctance transducers (DVRTs) from Microstrain were sutured into the subscapularis tendon-superior, inferior, and in line with the proposed 5 o'clock portal. The musculotendinous unit was loaded along its line of action with 3, 9, and then 15 kg. Strain at each DVRT was measured in the native subscapularis tendon at each load level. The same strain measurement was taken after placing and removing a 5-mm suture anchor through the 5 o'clock portal and in the tendon after placing and removing an 8-mm cannula.

Results: Penetrating the subscapularis tendon with either a 5-mm suture anchor or an 8-mm cannula does not produce any statistically significant change in strain compared with the native tendon.

Conclusion: Placing an anchor, or even an 8-mm cannulated portal, does not significantly alter the strain properties of the subscapularis tendon. This lack of effect on the strain characteristics of the subscapularis does not preclude the possibility of clinical effects.
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http://dx.doi.org/10.1016/j.jse.2010.07.019DOI Listing
January 2011

Shoulder arthroscopy in patients with a cardiac pacemaker or defibrillator: a case report and discussion of perioperative management.

J Shoulder Elbow Surg 2010 Dec 24;19(8):1204-9. Epub 2010 Jul 24.

Department of Orthopaedic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

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http://dx.doi.org/10.1016/j.jse.2010.04.040DOI Listing
December 2010

Lck mediates Th2 differentiation through effects on T-bet and GATA-3.

J Immunol 2010 Apr 17;184(8):4178-84. Epub 2010 Mar 17.

Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

The Src family kinase Lck has been shown to be crucial in T cell signaling and development. However, its role in Th effector functions is not well understood. Lck has previously been shown to play a role in the cytokine expression of Th2 cells, but the mechanism by which Lck influences Th2 effector functions is unknown. Using a mouse model, we report that Lck is important in regulating the expression of IL-4 in Th2 skewed cells but is not as necessary for the expression of Th2 cytokines IL-5, IL-10, and IL-13. Furthermore, in the absence of Lck, T-bet and GATA-3 expression is aberrant. Moreover, this atypical expression pattern of T-bet and GATA-3 correlates with increased histone 3 acetylation at the Ifng locus and production of the Th1 cytokine IFN-gamma. We find overexpression of GATA-3 restores IL-4 expression in lck(-/-) Th2 cells; this indicates that the decreased IL-4 expression is due in part to reduced amounts of GATA-3. Taken together, these data imply that Lck mediates Th2 differentiation through effects on T-bet and GATA-3.
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http://dx.doi.org/10.4049/jimmunol.0901282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889130PMC
April 2010

Engineering of stable bispecific antibodies targeting IL-17A and IL-23.

Protein Eng Des Sel 2010 Mar 18;23(3):115-27. Epub 2009 Dec 18.

ZymoGenetics, Inc., Seattle, WA 98102, USA.

Bispecific antibodies (bsAbs) present an attractive opportunity to combine the additive and potentially synergistic effects exhibited by combinations of monoclonal antibodies (mAbs). Current challenges for engineering bsAbs include retention of the binding affinity of the parent mAb or antibody fragment, the ability to bind both targets simultaneously, and matching valency with biology. Other factors to consider include structural stability and expression of the recombinant molecule, both of which may have significant impact on its development as a therapeutic. Here, we incorporate selection of stable, potent single-chain variable fragments (scFvs) early in the engineering process to assemble bsAbs for therapeutic applications targeting the cytokines IL-17A/A and IL-23. Stable scFvs directed against human cytokines IL-23p19 and IL-17A/A were isolated from a human Fab phage display library via batch conversion of panning output from Fabs to scFvs. This strategy integrated a step for shuffling V regions during the conversion and permitted the rescue of scFv molecules in both the V(H)V(L) and the V(L)V(H) orientations. Stable scFvs were identified and assembled into several bispecific formats as fusions to the Fc domain of human IgG1. The engineered bsAbs are potent neutralizers of the biological activity of both cytokines (IC(50) < 1 nM), demonstrate the ability to bind both target ligands simultaneously and display stability and productivity advantageous for successful manufacture of a therapeutic molecule. Pharmacokinetic analysis of the bsAbs in mice revealed serum half-lives similar to human mAbs. Assembly of bispecific molecules using stable antibody fragments offers an alternative to reformatting mAbs and minimizes subsequent structure-related and manufacturing concerns.
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http://dx.doi.org/10.1093/protein/gzp073DOI Listing
March 2010

IL-17 receptor signaling: ubiquitin gets in on the act.

Authors:
Steven D Levin

Sci Signal 2009 Oct 13;2(92):pe64. Epub 2009 Oct 13.

Department of Immunology, ZymoGenetics Inc., Seattle, WA 98102, USA.

Engagement of the interleukin-17 (IL-17) receptor complex triggers activation of the transcription factor nuclear factor kappaB (NF-kappaB). A wide array of signaling molecules can contribute to the activation of NF-kappaB, but a number of common themes link the receptors engaged to activate it with the translocation of the active complex to the nucleus; among these is a clear role for ubiquitination. Ubiquitination is essential to the degradation of the inhibitor of NF-kappaB (IkappaB) subunits, which otherwise retain the inactive NF-kappaB complex in the cytosol. However, additional roles for ubiquitination in the assembly of signaling complexes and in enzyme activation are underappreciated aspects of NF-kappaB induction pathways. These roles require a form of ubiquitination biochemically distinct from that which targets proteins for degradation. The identification of Act1, an adaptor protein of the IL-17 receptor, as an E3 ubiquitin ligase capable of initiating this modification provides an impressive connection between the IL-17 receptor complex and pathways that activate NF-kappaB.
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http://dx.doi.org/10.1126/scisignal.292pe64DOI Listing
October 2009

The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans.

J Exp Med 2009 Jul 15;206(7):1495-503. Epub 2009 Jun 15.

Molecular and Cell Based Discovery, ZymoGenetics Inc., Seattle, WA 98102, USA.

Cancer development is often associated with the lack of specific and efficient recognition of tumor cells by the immune system. Natural killer (NK) cells are lymphocytes of the innate immune system that participate in the elimination of tumors. We report the identification of a tumor cell surface molecule that binds NKp30, a human receptor which triggers antitumor NK cell cytotoxicity and cytokine secretion. This previously unannotated gene belongs to the B7 family and, hence, was designated B7-H6. B7-H6 triggers NKp30-mediated activation of human NK cells. B7-H6 was not detected in normal human tissues but was expressed on human tumor cells, emphasizing that the expression of stress-induced self-molecules associated with cell transformation serves as a mode of cell recognition in innate immunity.
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http://dx.doi.org/10.1084/jem.20090681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715080PMC
July 2009

Biomechanical analysis of bursal-sided partial thickness rotator cuff tears.

J Shoulder Elbow Surg 2009 May-Jun;18(3):379-85. Epub 2009 Mar 9.

Department of Orthopaedic Surgery, Northwestern University, Chicago, IL 60611, USA.

Background: Treatment of partial thickness supraspinatus tendon tears is controversial with no clearly defined treatment algorithms based on severity of tears. This study aims to evaluate the relationship between depth of partial thickness tears and strain.

Methods: Bursal-sided partial thickness tears were created at 1 mm increments in depth at the anterior portion of the supraspinatus tendon to 3/4 tendon width on ten fresh-frozen shoulder specimens. The supraspinatus muscle was dynamically loaded from 0-50N, and strain recorded at both the anterior and posterior portions of the tendon.

Results: Strain in the intact posterior portion increased monotonically with tear depth and supraspinatus force. Strain in the torn anterior portion decreased with increasing tear thickness and loading force. At 60% thickness tear, strain was significantly higher (P = 0.023) in the intact posterior portion compared to intact tendon. As the tear thickness exceeded 50% tendon thickness, the strain in the intact tendon rapidly increased nonlinearly.

Conclusions: Biomechanical results herein suggest increasing potential for tear propagation in the transverse plane with increasing depth of tears, and biomechanically supports repairs of grade III (>50% thickness).
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http://dx.doi.org/10.1016/j.jse.2008.12.011DOI Listing
July 2009

Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F.

J Immunol 2007 Oct;179(8):5462-73

Department of Molecular and Cell Based Discovery, ZymoGenetics Incroporated, Seattle, WA 98102, USA.

The proinflammatory cytokines IL-17A and IL-17F have a high degree of sequence similarity and share many biological properties. Both have been implicated as factors contributing to the progression of inflammatory and autoimmune diseases. Moreover, reagents that neutralize IL-17A significantly ameliorate disease severity in several mouse models of human disease. IL-17A mediates its effects through interaction with its cognate receptor, the IL-17 receptor (IL-17RA). We report here that the IL-17RA-related molecule, IL-17RC is the receptor for IL-17F. Notably, both IL-17A and IL-17F bind to IL-17RC with high affinity, leading us to suggest that a soluble form of this molecule may serve as an effective therapeutic antagonist of IL-17A and IL-17F. We generated a soluble form of IL-17RC and demonstrate that it effectively blocks binding of both IL-17A and IL-17F, and that it inhibits signaling in response to these cytokines. Collectively, our work indicates that IL-17RC functions as a receptor for both IL-17A and IL-17F and that a soluble version of this protein should be an effective antagonist of IL-17A and IL-17F mediated inflammatory diseases.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849293PMC
http://dx.doi.org/10.4049/jimmunol.179.8.5462DOI Listing
October 2007

Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice.

Nat Immunol 2004 Jul 6;5(7):752-60. Epub 2004 Jun 6.

Department of Immunology, ZymoGenetics, 1201 Eastlake Avenue East, Seattle, Washington 98102, USA.

T cell-derived cytokines are important in the development of an effective immune response, but when dysregulated they can promote disease. Here we identify a four-helix bundle cytokine we have called interleukin 31 (IL-31), which is preferentially produced by T helper type 2 cells. IL-31 signals through a receptor composed of IL-31 receptor A and oncostatin M receptor. Expression of IL-31 receptor A and oncostatin M receptor mRNA was induced in activated monocytes, whereas epithelial cells expressed both mRNAs constitutively. Transgenic mice overexpressing IL-31 developed severe pruritus, alopecia and skin lesions. Furthermore, IL-31 receptor expression was increased in diseased tissues derived from an animal model of airway hypersensitivity. These data indicate that IL-31 may be involved in promoting the dermatitis and epithelial responses that characterize allergic and non-allergic diseases.
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http://dx.doi.org/10.1038/ni1084DOI Listing
July 2004

Lck is required for activation-induced T cell death after TCR ligation with partial agonists.

J Immunol 2004 Feb;172(3):1437-43

Human Immunogenetics Program, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

TCR engagement can induce either T cell proliferation and differentiation or activation-induced T cell death (AICD) through apoptosis. The intracellular signaling pathways that dictate such a disparate fate after TCR engagement have only been partially elucidated. Non-FcR-binding anti-CD3 mAbs induce a partial agonist TCR signaling pattern and cause AICD on Ag-activated, cycling T cells. In this study, we examined TCR signaling during the induction of AICD by anti-CD3 fos, a non-FcR-binding anti-CD3 mAb. This mAb activates Fyn, Lck, and extracellular signal-regulated kinase, and induces phosphorylation of Src-like adapter protein, despite the inability to cause calcium mobilization or TCR polarization. Anti-CD3 fos also fails to effectively activate zeta-associated protein of 70 kDa or NF-kappaB. Using Ag-specific T cells deficient for Fyn or Lck, we provide compelling evidence that activation of Lck is required for the induction of AICD. Our data indicate that a selective and distinct TCR signaling pattern is required for AICD by TCR partial agonist ligands.
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http://dx.doi.org/10.4049/jimmunol.172.3.1437DOI Listing
February 2004

Requirement for cyclin D3 in lymphocyte development and T cell leukemias.

Cancer Cell 2003 Dec;4(6):451-61

Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.

The D-type cyclins (cyclins D1, D2, and D3) are components of the core cell cycle machinery in mammalian cells. Cyclin D3 gene is rearranged and the protein is overexpressed in several human lymphoid malignancies. In order to determine the function of cyclin D3 in development and oncogenesis, we generated and analyzed cyclin D3-deficient mice. We found that cyclin D3(-/-) animals fail to undergo normal expansion of immature T lymphocytes and show greatly reduced susceptibility to T cell malignancies triggered by specific oncogenic pathways. The requirement for cyclin D3 also operates in human malignancies, as knock-down of cyclin D3 inhibited proliferation of acute lymphoblastic leukemias deriving from immature T lymphocytes. These studies point to cyclin D3 as a potential target for therapeutic intervention in specific human malignancies.
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http://dx.doi.org/10.1016/s1535-6108(03)00301-5DOI Listing
December 2003

Regulation of Fyn through translocation of activated Lck into lipid rafts.

J Exp Med 2003 May;197(9):1221-7

Sunnybrook and Women's College Health Sciences Centre, and Departmentof Immunology, University of Toronto, Ontario M4N 3M5, Canada.

Whether or how the activation of Lck and Fyn during T cell receptor (TCR) signaling is coordinated, and their delivery of function integrated, is unknown. Here we show that lipid rafts function to segregate Lck and Fyn in T cells before activation. Coaggregation of TCR and CD4 leads to Lck activation within seconds outside lipid rafts, followed by its translocation into lipid rafts and the activation of colocalized Fyn. Genetic evidence demonstrates that Fyn activation is strictly dependent on receptor-induced translocation of Lck. These results characterize the interdependence of Lck and Fyn function and establish the spatial and temporal distinctions of their roles in the cellular activation process.
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http://dx.doi.org/10.1084/jem.20022112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193969PMC
May 2003

CD28 plays a critical role in the segregation of PKC theta within the immunologic synapse.

Proc Natl Acad Sci U S A 2002 Jul 20;99(14):9369-73. Epub 2002 Jun 20.

Division of Immunochemistry, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA.

The signaling pathways that lead to the localization of cellular protein to the area of interaction between T cell and antigen-presenting cell and the mechanism by which these molecules are further sorted to the peripheral supramolecular activation cluster or central supramolecular activation cluster regions of the immunologic synapse are poorly understood. In this study, we investigated the functional involvement of CD28 costimulation in the T cell receptor (TCR)-mediated immunologic synapse formation with respect to protein kinase C (PKC)theta; localization. We showed that CD3 crosslinking alone was sufficient to induce PKC theta; capping in naive CD4(+) T cells. Studies with pharmacologic inhibitors and knockout mice showed that the TCR-derived signaling that drives PKC theta; membrane translocation requires the Src family kinase, Lck, but not Fyn. In addition, a time course study of the persistence of T cell molecules to the immunologic synapse indicated that PKC theta;, unlike TCR, persisted in the synapse for at least 4 h, a time that is sufficient for commitment of a T cell to cell division. Finally, by using TCR-transgenic T cells from either wild-type or CD28-deficient mice, we showed that CD28 expression was required for the formation of the mature immunologic synapse, because antigen stimulation of CD28(-) T cells led to a diffuse pattern of localization of PKC theta; and lymphocyte function-associated antigen-1 in the immunologic synapse, in contrast to the central supramolecular activation cluster localization of PKC theta; in CD28(+) T cells.
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http://dx.doi.org/10.1073/pnas.142298399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC123147PMC
July 2002

Uncoupling of proliferation and Stat5 activation in thymic stromal lymphopoietin-mediated signal transduction.

J Immunol 2002 Apr;168(7):3288-94

Virginia Mason Research Center, Seattle, WA 98101, USA.

Thymic stromal lymphopoietin (TSLP) is a cytokine that facilitates B lymphocyte differentiation and costimulates T cells. Previous studies have demonstrated that a functional TSLP receptor complex is a heterodimer consisting of the TSLP receptor and the IL-7R alpha-chain. TSLP-mediated signaling is unique among members of the cytokine receptor family in that activation of the transcription factor Stat5 occurs without detectable Janus kinase activation. Using a variety of biological systems we demonstrate here that TSLP-mediated Stat5 activation can be uncoupled from proliferation. We also show that the single tyrosine residue in the cytoplasmic domain of the TSLP receptor is critical for TSLP-mediated proliferation, but is dispensable for Stat5 activation. Our data demonstrate that TSLP-mediated Stat5 activation is insufficient for cell proliferation and identifies residues within the TSLP receptor complex required to mediate these downstream events.
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http://dx.doi.org/10.4049/jimmunol.168.7.3288DOI Listing
April 2002