A5045674790- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Virus-based gene therapy research
- Immune cells in cancer
- Cancer Immunotherapy and Biomarkers
- Redox biology and oxidative stress
- Cell death mechanisms and regulation
- Immune Response and Inflammation
- Sphingolipid Metabolism and Signaling
- Research on Leishmaniasis Studies
- Adenosine and Purinergic Signaling
- Cancer Research and Treatments
- Mitochondrial Function and Pathology
- Mesenchymal stem cell research
- dental development and anomalies
- Monoclonal and Polyclonal Antibodies Research
- Periodontal Regeneration and Treatments
- interferon and immune responses
- Viral Infectious Diseases and Gene Expression in Insects
- Cytomegalovirus and herpesvirus research
Medical University of South Carolina
2012-2019
MUSC Hollings Cancer Center
2014-2019
National Institute of Immunology
2010-2017
College of Charleston
2015
Sphingosine 1-phosphate (S1P), a bioactive lysophospholipid generated by sphingosine kinase 1 (SphK1), regulates lymphocyte egress into circulation via S1P receptor (S1PR1) signaling, and it controls the differentiation of regulatory T cells (Tregs) helper-17 cells. However, mechanisms which receptor-independent SphK1-mediated intracellular levels modulate cell functionality remains unknown. We show here that SphK1-deficient maintain central memory phenotype exhibit higher mitochondrial...
T cells of the helper (Th)17 subset offer promise in adoptive T-cell therapy for cancer. However, current protocols ex vivo programming Th17 cells, which include TGFβ exposure, increase expression CD39 and CD73, two cell surface ATP ectonucleotidases that reduce effector functions promote immunosuppression. Here, we report ATP-mediated suppression IFNγ production by can be overcome genetic ablation CD73 or using IL1β instead to program vivo. cultured were also highly polyfunctional,...
The inducible costimulator (ICOS) plays a key role in the development of Th17 cells, but its and antitumor activity IL-17-producing CD8(+) T cells (Tc17) remains unknown. We found that ICOS costimulation was important for functional maintenance, not differentiation, Tc17 vitro. Blocking pathway using an antagonist mAb or by recipient mice genetically deficient ligand reduced adoptively transferred cells. Conversely, activating with agonist vitro enhanced their capacity to eradicate melanoma...
Abstract Ex vivo–expanded CD8+ T cells used for adoptive immunotherapy generally acquire an effector memory-like phenotype (TEM cells). With regard to therapeutic applications, two undesired features of this in vivo are limited persistence and reduced antitumor efficacy, relative with a central (TCM Furthermore, there is incomplete knowledge about all the differences between TEM TCM that may influence tumor treatment outcomes. Given survive relatively longer oxidative microenvironments, we...
Abstract Repetitive stimulation of T-cell receptor (TCR) with cognate antigen results in robust proliferation and expansion the T cells, also imprints them replicative senescence signatures. Our previous studies have shown that life-span antitumor function cells can be enhanced by inhibiting reactive oxygen species (ROS) or intervening ROS-dependent JNK activation leads to its activation-induced cell death. Because tumor suppressor protein p53 is a redox active transcription factor regulates...
Abstract T cell response magnitudes increase with increasing antigenic dosage. However, it is unclear whether ligand density only modulates the proportions of responding ligand-specific cells or also alters responses at single level. Using brief (3 h) exposure TCR-transgenic mouse CD8 in vitro to varying densities cognate peptide-MHC followed by ligand-free culture IL-2, we found that determined frequencies but not expression levels early activation marker molecule, CD69. Cells low glucose...
Apoptosis-inducing factor (Aif) is a mitochondrial flavoprotein that regulates cell metabolism and survival in many tissues. We report aif-hypomorphic harlequin (Hq) mice show thymic hypocellularity cell-autonomous thymocyte developmental block associated with apoptosis at the β-selection stage, independent of T receptor β recombination. No abnormalities are observed B lineage. Transgenes encoding wild-type or DNA-binding–deficient mutant Aif rectify defect, but transgene oxidoreductase...
Improving persistence and sustained function of effector CD8+ T cell response is key for achieving significant tumor control in adoptive immunotherapy protocols. Our recent report shows that high anti-oxidant property central to potent anti-tumor cells, directly correlates CD62Lhi memory, low glycolytic mitochondrial membrane potential phenotype, all which may be linked contribute better control.
While earlier studies have suggested that cells positive for hematopoietic markers can be found in dental tissues, it has yet to confirmed. To conclusively demonstrate this, we utilized a unique transgenic model which all are green fluorescent protein+ (GFP+). Pulp, periodontal ligament (PDL) and alveolar bone (AvB) cell culture analysis demonstrated numerous GFP+ cells, were also CD45+ (indicating origin) co-expressed of cellular populations pulp (dentin matrix protein-1, dentin...
Germ-line retroviral insertions in vertebrate genomes are implicated the modulation of host immune responses. We demonstrate that CBA/J mice, which carry proviral integrants mammary tumor virus locus 6 (Mtv6) and 7 (Mtv7), less resistant to infection with protozoan pathogen Leishmania major compared closely related but Mtv6-negative Mtv7-negative CBA/CaJ mice. Although both strains generated comparable L. major-specific CD4 T cell frequencies, cells from mice made much interferon γ (IFN-γ)....
Abstract Amongst various effector CD4+ T cells, helper (Th)-17 subsets hold promise in adoptive cell transfer therapy for cancer. However, ex vivo programming of Th17 cells presence TGF-β increases surface expression ectonucleotidases CD39 and CD73, that turn susceptibility to immunosuppression reduced phenotype. Our data shows ATP mediated suppression IFN-γ production by can be overcome either genetic ablation CD73 or generating independent IL-1β. An comparison anti-tumor potential between...
Abstract Sphingosine kinase 1(Sphk1) is a key enzyme in sphingolipid metabolism that involved the production of sphingosine-1-phosphate (S1P). S1P controls many cellular processes such as cell proliferation, migration and cytokine production. We sought to address role Sphk1 regulating T responses tumor specific ‘self’ antigen gp100, mouse model melanoma by generating TCR transgenic mice pMel on deficient background. found Sphk1-/-pMel showed reduced progression subcutaneous administration...
Abstract Various effects of altered p53 expression are known with reference to uncontrolled cell proliferation, senescence and death. Loss also induces spontaneous inflammatory lesion Treg deficiency. Only minor differences in apoptosis, maintenance ‘non-self’ viral antigen specific T cells have been previously reported. However, the role controlling response ‘self’ tumor epitope has not comprehensively investigated. The h3T TCR transgenic mice human tyrosinase reactive were thus developed...
Abstract Adoptive transfer of tumor epitope reactive T cells is a promising strategy to control growth. However, chronically stimulated expanded for adoptive cell (ACT) are susceptible death in an oxidative microenvironment. Since oxidation surface thiols (c-SH) also alters functionality proteins, we hypothesized that increased level thioredoxin, anti-oxidant molecule facilitates reduction proteins by cysteine thiol-disulfide exchange, will result sustained anti-tumor function. We thus...
Abstract Upon brief exposure to antigenic stimulation, naïve CD8+ T lymphocytes execute an autonomous programme of several rounds proliferation and maturation into effector cytotoxic cells. We have studied the role ligand density as a modifier this program using cell receptor (TCR)-transgenic activation by short-duration stimulation in vitro. Over entire range studied, we observe graded increase frequency responder cells that upregulate expression CD69, early marker. However, levels induced...
Abstract Thymocytes undergo a number of selection events before egressing the thymus and moving to lymphoid organs as mature T cells. The chronology these molecular cellular is crucial for determining function We have established transgenic mouse model using CD8 independent human TIL1383I αβTCR that was isolated from MHC I restricted CD4+ cells obtained tumor infiltrating lymphocytes metastatic melanoma patient recognizes tyrosinase epitope presented by HLA-A2. analyzed cell fate thymocytes...
Abstract Functional heterogeneity in apparently homogenous T cell populations has been well reported. However, what factors lead to such variations within a population is still unclear. Depending upon the time of egress from thymus and duration residence periphery, individual cells would be relatively different ages, however, consequences cellular aging have not addressed. We observed that naive CD8 aged mice lower coreceptor levels than young mice. Further, when are separated into...