A5011939041- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- Cell Adhesion Molecules Research
- Diabetes and associated disorders
- Cancer Immunotherapy and Biomarkers
- Pancreatic function and diabetes
- Immune Response and Inflammation
- Genetic Neurodegenerative Diseases
- CAR-T cell therapy research
- Mitochondrial Function and Pathology
- RNA Research and Splicing
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Diabetes Management and Research
- Single-cell and spatial transcriptomics
- Cell Image Analysis Techniques
- Glycosylation and Glycoproteins Research
- Cardiac Valve Diseases and Treatments
- Cardiac, Anesthesia and Surgical Outcomes
- Platelet Disorders and Treatments
- Hematopoietic Stem Cell Transplantation
- Immune cells in cancer
- Complement system in diseases
- Aquatic Invertebrate Ecology and Behavior
University of Minnesota
2015-2024
University of Minnesota Medical Center
2011-2024
Institute of Immunology
2017-2022
University of Colorado Denver
2020
Imaging Center
2018-2019
Georgia Department of Natural Resources
2012
The University of Texas MD Anderson Cancer Center
2002-2009
North Shore Medical Center
1997
Type 1 diabetes is caused by autoreactive T cell-mediated β cell destruction. Even though co-inhibitory receptor programmed death-1 (PD-1) restrains autoimmunity, the expression and regulation of its cognate ligands on remains unknown. Here, we interrogated cell-intrinsic death ligand-1 (PD-L1) in mouse human islets. We measured a significant increase level PD-L1 surface frequency
Numerous observations indicate that resident memory T cells (TRM) undergo unusually rapid attrition within the lung. Here we demonstrate contraction of lung CD8+ cell responses after influenza infection is contemporized with egress CD69+/CD103+ to draining mediastinal LN via lymphatic vessels, which term retrograde migration. Cells retained canonical markers TRM, including CD103 and CD69, lacked Ly6C expression (also a feature TRM), maintained granzyme B expression, did not equilibrate among...
Respiratory tract resident memory T cells (T
Adoptive immunotherapy with Tregs is a promising approach for prevention or treatment of type 1 diabetes. Islet antigen-specific have more potent therapeutic effects than polyclonal cells, but their low frequency barrier clinical application. To generate that recognize islet antigens, we engineered chimeric antigen receptor (CAR) derived from monoclonal antibody specificity the insulin B-chain 10-23 peptide presented in context IAg7 MHC class II allele present NOD mice. Peptide resulting...
WAVE2 regulates T cell receptor (TCR)–stimulated actin cytoskeletal dynamics leading to both integrin clustering and affinity maturation. Although mediates maturation by recruiting vinculin talin the immunological synapse in an Arp2/3-dependent manner, mechanism which it is unclear. We show that Abl tyrosine kinase associates with complex TCR ligation induces WAVE2-dependent membrane recruitment of Abl. Furthermore, we TCR-mediated activation regulatory guanosine triphosphatase Rap1 via...
Naive CD4+ T lymphocytes differentiate into various Th cell subsets following TCR binding to microbial peptide:MHC class II (p:MHCII) complexes on dendritic cells (DCs). The affinity of the interaction with p:MHCII plays a role in differentiation by mechanisms that are not completely understood. We found low-affinity TCRs biased mouse naive become follicular helper (Tfh) cells, whereas higher-affinity promoted formation Th1 or Th17 cells. explored basis for this phenomenon focusing IL-2R...
T-cell-receptor (TCR)-mediated integrin activation is required for T-cell-antigen-presenting cell conjugation and adhesion to extracellular matrix components. While it has been demonstrated that the actin cytoskeleton its regulators play an essential role in this process, no mechanism established which directly links TCR-induced polymerization of integrins. Here, we demonstrate TCR stimulation results WAVE2-ARP2/3-dependent F-actin nucleation formation a complex containing WAVE2, ARP2/3,...
The alpha4beta7 integrin promotes homing of T cells to intestinal sites. alpha4 subunit that pairs with beta7 can also pair beta1 integrin. In this paper, we show the preferential pairing regulates expression on cells. absence integrin, naive mouse CD4 have increased expression, resulting in adhesion mucosal addressin cell molecule-1 and enhanced Peyer's patches (PP). a reciprocal manner, overexpression causes loss decreased PP. A similar upregulation suppression occurs rapidly after...
Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the widely expressed ataxin-1 (ATXN1) protein. To elucidate anatomical regions and cell types that underlie mutant ATXN1-induced phenotypes, we developed floxed conditional knockin mouse (f-ATXN1146Q/2Q) with Atxn1 coding exons replaced human ATXN1 encoding 146 glutamines. f-ATXN1146Q/2Q mice manifested SCA1-like phenotypes including motor cognitive deficits, wasting,...
Regulatory T cells (Tregs) are critical for maintaining immune homeostasis. However, current Treg immunotherapies do not optimally treat inflammatory diseases in patients. Understanding the cellular processes that control function may allow augmentation of therapeutic efficacy. In contrast to activated conventional cells, which protein kinase C-θ (PKC-θ) localizes contact point between and antigen-presenting human mouse Tregs, PKC-θ opposite end cell distal pole complex (DPC). Here, using a...
Adoptive immunotherapy with Tregs is a promising approach for prevention or treatment of type 1 diabetes. Islet antigen-specific have more potent therapeutic effects than polyclonal cells, but their low frequency barrier clinical application. To generate that recognize islet antigens, we engineered chimeric antigen receptor (CAR) derived from monoclonal antibody specificity the insulin B-chain 10-23 peptide presented in context IA
Influenza viruses pose a significant burden on global human health. has broad cellular tropism in the airway, but how infection of different epithelial cell types impacts replication kinetics and airways is not fully understood. Using primary airway cultures, which recapitulate diverse landscape airways, we investigated impact type composition virus kinetics. Cultures were highly across multiple donors 30 independent differentiation conditions supported range influenza replication. Although...
The role of PI-3K in leukocyte function has been studied extensively. However, the specific p110gamma isoform PI- 3K CD4 T lymphocyte yet to be defined explicitly. In this study, we report that although does not regulate antigen-dependent cell activation and proliferation, it plays a crucial regulating effector migration. Naïve p110gamma(-/-) lymphocytes are phenotypically identical their wild-type (WT) counterparts do exhibit any defects TCR-mediated calcium mobilization or Erk activation....
Optimal ex vivo expansion protocols of tumor-specific T cells followed by adoptive cell therapy must yield able to home tumors and effectively kill them. Our previous study demonstrated activation in the presence IL-12-induced optimal CD8+ melanoma regression; however, adverse side effects, including autoimmunity, can occur. This may be due transfer high-avidity self-specific cells. In this study, we compared mouse low- targeting tumor Ag tyrosinase-related protein 2 (TRP2). Not...
Abstract The study of lipid microdomains in the plasma membrane is a topic recent interest leukocyte biology. Many T cell activation and signaling molecules are found to be associated with have been implicated normal function. It has proposed that their move by lateral diffusion areas cellular interactions initiate pathways. Using sucrose density gradients we human β1 integrins not normally microdomains. However, cross-linking GM1 through cholera toxin B-subunit (CTB) causes an enrichment...
Lipid rafts are small laterally mobile microdomains that highly enriched in lymphocyte signaling molecules. GM1 gangliosides a common lipid raft component and have been shown to be important many T-cell functions. The aggregation of specific can control activation events, including their novel association with integrins. We found clustering regulate beta1 integrin function. This was apparent through increased resistance shear flow-dependent detachment T cells adherent the alpha4beta1...
The migratory capacity of adaptive CD8αβ T cells dictates their ability to locate target and exert cytotoxicity, which is the basis immune surveillance for containment microbes disease. small intestine (SI) largest mucosal surface a primary site pathogen entrance. Using two-photon laser scanning microscopy, we found that motility antigen (Ag)-specific in SI dynamic varies with environmental milieu. Pathogen-specific cell movement differed throughout infection, becoming locally confined at...
Programmed death-1 (PD-1) inhibits T and B cell function upon ligand binding. PD-1 blockade revolutionized cancer treatment, although numerous patients respond, some develop autoimmune-like symptoms or overt autoimmunity characterized by autoantibody production. inhibition accelerates in mice, but its role regulating germinal centers (GC) is controversial. To address the of GC reaction type 1 diabetes, we used tetramers to phenotype insulin-specific CD4+ cells NOD mice. PD-L1 deficiency, not...
We investigate how myeloid subsets differentially shape immunity to pancreatic ductal adenocarcinoma (PDA). show that tumor antigenicity sculpts cell composition and functionality. Antigenicity promotes accumulation of type 1 dendritic cells (cDC1), which is driven by Xcr1 signaling, overcomes macrophage-mediated suppression. The therapeutic activity adoptive T therapy or programmed death ligand blockade required cDC1s, sustained splenic Klrg1+ cytotoxic antitumor functional intratumoral...
Cell adhesion mediated by the interaction between integrin alpha4beta1 and VCAM-1 is important in normal physiologic processes inflammatory autoimmune disease. Numerous studies have mapped binding sites that mediate cell adhesion; however, little known about regions for regulating soluble binding. In present study, we demonstrate 6D (an alternatively spliced isoform of lacking Ig-like domain 4) binds with a higher relative affinity than does full-length form containing 7 extracellular...
Abstract Adhesion and degranulation promoting adapter protein (ADAP) is a multifunctional hematopoietic that regulates TCR-dependent increases in both integrin function activation of the NF-κB transcription factor. Activation requires ADAP ADAP-associated Src kinase-associated phosphoprotein 55 kDa (SKAP55). In contrast, ADAP-mediated regulation involves distinct binding sites promote inducible association ADAP, but not SKAP55, with CARMA1 TAK1 kinase. This suggests presence or absence...