A5035163409- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Cellular Mechanics and Interactions
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Cell Adhesion Molecules Research
- Monoclonal and Polyclonal Antibodies Research
- Cancer Immunotherapy and Biomarkers
- Cellular transport and secretion
- Immunodeficiency and Autoimmune Disorders
- Viral gastroenteritis research and epidemiology
- Cytokine Signaling Pathways and Interactions
- Lipid Membrane Structure and Behavior
- Immune cells in cancer
- Fish Biology and Ecology Studies
- Erythrocyte Function and Pathophysiology
- Force Microscopy Techniques and Applications
- HIV Research and Treatment
- interferon and immune responses
- Cell Image Analysis Techniques
- Pesticide Exposure and Toxicity
- Virus-based gene therapy research
- RNA Interference and Gene Delivery
- Cytomegalovirus and herpesvirus research
- Synthesis of Tetrazole Derivatives
Indian Institute of Science Bangalore
2021-2024
Massachusetts Institute of Technology
2015-2023
Ganesh Shankar Vidyarthi Memorial Medical College
2021-2023
Cancer Institute (WIA)
2023
Ragon Institute of MGH, MIT and Harvard
2016-2020
New York University
2010-2020
Indian Institute of Technology Delhi
2020
Koch Institute for Integrative Cancer Research At MIT
2015-2019
Allen Institute
2015-2019
Robert Koch Institute
2018
Chimeric antigen receptor-T cell (CAR-T) therapy has been effective in the treatment of hematologic malignancies, but it shown limited efficacy against solid tumors. Here we demonstrate an approach to enhancing CAR-T function tumors by directly vaccine-boosting donor cells through their chimeric receptor vivo. We designed amphiphile ligands (amph-ligands) that, upon injection, trafficked lymph nodes and decorated surfaces antigen-presenting cells, thereby priming CAR-Ts native node...
Natural infections expose the immune system to escalating antigen and inflammation over days weeks, whereas nonlive vaccines are single bolus events. We explored whether responds optimally kinetics most similar replicating infections, rather than a dose. Using HIV antigens, we found that administering given total dose of adjuvant 1-2 wk through repeated injections or osmotic pumps enhanced humoral responses, with exponentially increasing (exp-inc) dosing profiles eliciting >10-fold increases...
T cell receptor (TCR)-dependent regulatory (Treg) activity controls effector (Teff) function and is inhibited by the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Protein kinase C-theta (PKC-theta) recruitment to immunological synapse required for full Teff activation. In contrast, PKC-theta was sequestered away from Treg synapse. Furthermore, blockade enhanced function, demonstrating inhibits Treg-mediated suppression. Inhibition of protected inactivation TNF-alpha,...
In vaccine design, antigens are often arrayed in a multivalent nanoparticle form, but vivo mechanisms underlying the enhanced immunity elicited by such vaccines remain poorly understood. We compared fates of two different heavily glycosylated HIV antigens, gp120-derived mini-protein and large, stabilized envelope trimer, protein or "free" forms after primary immunization. Unlike monomeric nanoparticles were rapidly shuttled to follicular dendritic cell (FDC) network then concentrated...
Wiscott Aldrich Syndrome protein (WASP) deficiency results in defects calcium ion signaling, cytoskeletal regulation, gene transcription and overall T cell activation. The activation of WASP constitutes a key pathway for actin filament nucleation. Yet, when function is eliminated there negligible effect on polymerization at the immunological synapse, leading to gaps our understanding events connecting signaling. Here, we identify fraction total synaptic F-actin selectively generated by form...
Adoptive cell therapy (ACT) has achieved striking efficacy in B-cell leukemias, but less success treating other cancers, part due to the rapid loss of ACT T-cell effector function vivo immunosuppression solid tumors. Transforming growth factor-β (TGF-β) signaling is an important mechanism immune suppression tumor microenvironment, systemic inhibition TGF-β toxic. Here we evaluated potential targeting a small molecule inhibitor T-cells using PEGylated immunoliposomes. Liposomes were prepared...
Wiskott-Aldrich syndrome (WAS) is associated with mutations in the WAS protein (WASp), which plays a critical role initiation of T cell receptor-driven (TCR-driven) actin polymerization. The clinical phenotype includes susceptibility to infection, allergy, autoimmunity, and malignancy overlaps symptoms dedicator cytokinesis 8 (DOCK8) deficiency, suggesting that 2 syndromes share common pathogenic mechanisms. Here, we demonstrated WASp-interacting (WIP) bridges DOCK8 WASp cells. We determined...
Cytoskeletal actin dynamics is essential for T cell activation. Here, we show evidence that the binding kinetics of antigen engaging receptor influences nanoscale organization and mechanics immune synapse. Using an engineered system expressing a specific stimulated by range antigens, found peak force experienced during activation was independent unbinding stimulating antigen. Conversely, quantification retrograde flow velocity at synapse revealed striking dependence on kinetics. These...
In the process of internalization molecules from extracellular milieu, a cell uses multiple endocytic pathways, consequently generating different vesicles. These primary vesicles are targeted to specific destinations inside cell. Here, we show that GPI-anchored proteins internalized by an Arf6-independent mechanism into protein-enriched early endosomal compartments (GEECs). Internalized and fluid phase first visualized in GEECs acidic, structures, negative for markers, Rab4, Rab5, endosome...
The hepatitis E virus (HEV) causes acute viral hepatitis, but its characterization is hampered by the lack of an efficient in vitro infection system that can be used to study effects HEV proteins on cellular processes. Previous studies suggest ORF3 protein (pORF3) essential for vivo and likely modulate host response. Here, we report pORF3 localizes early recycling endosomes a delay postinternalization trafficking epidermal growth factor receptor (EGFR) late endosomes/lysosomes. cytoplasmic...
Micropatterning of T cell ligands reveals their specific contributions to actin assembly and the generation cytoskeletal forces in immunesynapse formation.
Article2 January 2020Open Access Cytoskeletal tension actively sustains the migratory T-cell synaptic contact Sudha Kumari Corresponding Author [email protected] orcid.org/0000-0001-7082-2825 Koch Institute of Integrative Research, MIT, Cambridge, MA, USA Ragon Harvard, MIT and MGH, Search for more papers by this author Michael Mak Department Mechanical Engineering, Yeh-Chuin Poh orcid.org/0000-0003-3510-6369 Mira Tohme Division Immunology, Boston Children's Hospital, Harvard Medical School,...
Endocytosis of the nicotinic acetylcholine receptor (AChR) is a proposed major mechanism neuromodulation at neuromuscular junctions and in pathology synapses central nervous system. We show that binding competitive antagonist α-bungarotoxin (αBTX) or antibody-mediated cross-linking induces internalization cell surface AChR to late endosomes when expressed heterologously Chinese hamster ovary cells endogenously C2C12 myocytes. Internalization occurs via sequestration AChR–αBTX complexes...
In mammalian cells, endocytosis of the fluid phase and glycosylphosphatidylinositol-anchored proteins (GPI-APs) forms GEECs (GPI-AP enriched early endosomal compartments) via an Arf1- Cdc42-mediated, dynamin independent mechanism. Here we use four different fluorescently labeled probes several markers in combination with quantitative kinetic assays, RNA interference high resolution imaging to delineate major endocytic routes Drosophila cultured cells. We find that hallmarks pinocytic GEEC...
ORIGINAL RESEARCH article Front. Immunol., 17 August 2012Sec. T Cell Biology Volume 3 - 2012 | https://doi.org/10.3389/fimmu.2012.00230
Foxp3 + CD4 CD25 high regulatory T cell (Treg) suppression of inflammation depends on T-cell receptor-mediated Nuclear Factor Activated cells c1 (NFATc1) activation with reduced Akt activity. We investigated the role scaffold protein Disc large homolog 1 (Dlgh1) in linking receptor to this unique signaling outcome. The Treg immunological synapse (IS) recruited fourfold more Dlgh1 than conventional IS. Tregs isolated from patients active rheumatoid arthritis, or treated tumor necrosis...
Cytoskeletal actin dynamics are crucial for the activation of T-cells. Immortalised Jurkat T-cells have been model system choice to examine and correlate cytoskeleton immunological synapse leading T-cell activation. However, it has remained unclear whether immortalised cellular systems, such as can recapitulate cytoskeletal behaviour primary Studies delineating in comparison lacking. Here, we employ live-cell super-resolution microscopy investigate organisation living at appropriate...
Ovarian cancer (OC) is the third most common gynecological and alone has an emergence rate of approximately 308,069 cases worldwide (2020) with dire survival rates. To put it into perspective, mortality OC three times higher than that breast predicted to only increase significantly by 2040. The primary reasons for such a high are physical symptoms detectable during advanced phase disease when resistance chemotherapies around 80% patients do indeed respond chemotherapy initially, show poor...
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...