7 results on '"White, J. Michael"'
Search Results
2. Tuning T Cell Signaling Sensitivity Alters the Behavior of CD4 + T Cells during an Immune Response.
- Author
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Milam AAV, Bartleson JM, Donermeyer DL, Horvath S, Durai V, Raju S, Yu H, Redmann V, Zinselmeyer B, White JM, Murphy KM, and Allen PM
- Subjects
- Animals, CD5 Antigens immunology, Lymphocyte Activation immunology, Mice, Mice, Inbred C57BL, NAV1.5 Voltage-Gated Sodium Channel immunology, Receptors, Antigen, T-Cell immunology, CD4-Positive T-Lymphocytes immunology
- Abstract
Intricate processes in the thymus and periphery help curb the development and activation of autoreactive T cells. The subtle signals that govern these processes are an area of great interest, but tuning TCR sensitivity for the purpose of affecting T cell behavior remains technically challenging. Previously, our laboratory described the derivation of two TCR-transgenic CD4 T cell mouse lines, LLO56 and LLO118, which recognize the same cognate Listeria epitope with the same affinity. Despite the similarity of the two TCRs, LLO56 cells respond poorly in a primary infection whereas LLO118 cells respond robustly. Phenotypic examination of both lines revealed a substantial difference in their surface of expression of CD5, which serves as a dependable readout of the self-reactivity of a cell. We hypothesized that the increased interaction with self by the CD5-high LLO56 was mediated through TCR signaling, and was involved in the characteristic weak primary response of LLO56 to infection. To explore this issue, we generated an inducible knock-in mouse expressing the self-sensitizing voltage-gated sodium channel Scn5a. Overexpression of Scn5a in peripheral T cells via the CD4-Cre promoter resulted in increased TCR-proximal signaling. Further, Scn5a-expressing LLO118 cells, after transfer into BL6 recipient mice, displayed an impaired response during infection relative to wild-type LLO118 cells. In this way, we were able to demonstrate that tuning of TCR sensitivity to self can be used to alter in vivo immune responses. Overall, these studies highlight the critical relationship between TCR-self-pMHC interaction and an immune response to infection., (Copyright © 2018 by The American Association of Immunologists, Inc.)
- Published
- 2018
- Full Text
- View/download PDF
3. Identifying the initiating events of anti-Listeria responses using mice with conditional loss of IFN-γ receptor subunit 1 (IFNGR1).
- Author
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Lee SH, Carrero JA, Uppaluri R, White JM, Archambault JM, Lai KS, Chan SR, Sheehan KC, Unanue ER, and Schreiber RD
- Subjects
- Animals, Antigens, Ly metabolism, CD8 Antigens metabolism, Dendritic Cells immunology, Dendritic Cells metabolism, Interleukin-12 biosynthesis, Interleukin-4 biosynthesis, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Natural Killer T-Cells immunology, Natural Killer T-Cells metabolism, Receptors, Interferon deficiency, Receptors, Interferon genetics, Tumor Necrosis Factor-alpha metabolism, Interferon gamma Receptor, Interferon-gamma immunology, Interleukin-12 immunology, Listeria monocytogenes immunology, Listeriosis immunology, Receptors, Interferon immunology
- Abstract
Although IFN-γ is required for resolution of Listeria monocytogenes infection, the identities of the IFN-γ-responsive cells that initiate the process remain unclear. We addressed this question using novel mice with conditional loss of IFN-γR (IFNGR1). Itgax-cre(+)Ifngr1(f/f) mice with selective IFN-γ unresponsiveness in CD8α(+) dendritic cells displayed increased susceptibility to infection. This phenotype was due to the inability of IFN-γ-unresponsive CD8α(+) dendritic cells to produce the initial burst of IL-12 induced by IFN-γ from TNF-α-activated NK/NKT cells. The defect in early IL-12 production resulted in increased IL-4 production that established a myeloid cell environment favoring Listeria growth. Neutralization of IL-4 restored Listeria resistance in Itgax-cre(+)Ifngr1(f/f) mice. We also found that Itgax-cre(+)Ifngr1(f/f) mice survived infection with low-dose Listeria as the result of a second wave of IL-12 produced by Ly6C(hi) monocytes. Thus, an IFN-γ-driven cascade involving CD8α(+) dendritic cells and NK/NKT cells induces the rapid production of IL-12 that initiates the anti-Listeria response.
- Published
- 2013
- Full Text
- View/download PDF
4. T cell-mediated delay of spontaneous mammary tumor onset: increased efficacy with in vivo versus in vitro activation.
- Author
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O'Mara LA, Norian LA, Kreamalmeyer D, White JM, and Allen PM
- Subjects
- Animals, Antigens, Neoplasm, Autoantigens, Base Sequence, DNA, Recombinant genetics, Female, Immune Tolerance, Immunotherapy, Adoptive, In Vitro Techniques, Lymphocyte Activation, Mammary Neoplasms, Experimental therapy, Mice, Mice, Inbred BALB C, Mice, Transgenic, Mammary Neoplasms, Experimental etiology, Mammary Neoplasms, Experimental immunology, T-Lymphocytes immunology
- Abstract
Peripheral tolerance to shared Ags expressed on both tumors and normal self-tissues presents a major barrier to T cell-based immunotherapy as a treatment for cancer. To assess the activity of tumor-specific T cells against spontaneously arising carcinomas in the context of shared Ag expression, we developed a model system whereby an identified tumor Ag, tumor ERK (tERK), is expressed transgenically on both normal mammary tissue and spontaneous mammary carcinomas. Transfer of in vitro-activated, tERK-specific DUC18 T cells delayed spontaneous tumor development in tERK-expressing mice when T cells were given before the development of palpable carcinomas. However, antitumor activity mediated by in vitro-activated DUC18 T cells, as measured by responsiveness against a transplanted tERK-expressing fibrosarcoma challenge, was lost within days of transfer. This loss was due to expression of tERK as a self-Ag on normal tissues and was independent of the presence of mammary tumors. In contrast, transferred naive DUC18 T cells maintained a long-term protective function in tERK-expressing mice. Ten-fold fewer naive T cells activated in vivo were able to replicate the delay in spontaneous tumor development achieved by in vitro-activated T cells. These results are in contrast to our earlier studies using transplanted tumors alone, in which in vitro-activated DUC18 T cells were more efficacious than naive DUC18 T cells and highlight the need to perform tumor studies in the presence of tumor Ag expression on normal self-tissue.
- Published
- 2005
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- View/download PDF
5. MAPK p38 alpha is dispensable for lymphocyte development and proliferation.
- Author
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Kim JM, White JM, Shaw AS, and Sleckman BP
- Subjects
- Animals, B-Lymphocyte Subsets cytology, B-Lymphocyte Subsets enzymology, B-Lymphocyte Subsets immunology, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes enzymology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes enzymology, CD8-Positive T-Lymphocytes immunology, Cell Differentiation genetics, Cell Differentiation immunology, Cell Line, Crosses, Genetic, Embryo, Mammalian, Female, Flow Cytometry, Genetic Carrier Screening, Homozygote, Immunophenotyping, Isoenzymes biosynthesis, Isoenzymes deficiency, Isoenzymes physiology, Mice, Spleen cytology, Spleen enzymology, Spleen immunology, Stem Cells cytology, Stem Cells enzymology, Stem Cells immunology, p38 Mitogen-Activated Protein Kinases biosynthesis, p38 Mitogen-Activated Protein Kinases physiology, Cell Proliferation, Lymphopoiesis genetics, Lymphopoiesis immunology, p38 Mitogen-Activated Protein Kinases deficiency
- Abstract
Signals mediated by the p38alpha MAPK have been implicated in many processes required for the development and effector functions of innate and adaptive immune responses. As mice deficient in p38alpha exhibit embryonic lethality, most analyses of p38alpha function in lymphocytes have relied on the use of pharmacologic inhibitors and dominant-negative or constitutively active transgenes. In this study, we have generated a panel of low passage p38alpha(+/+), p38alpha(+/-), and p38alpha(-/-) embryonic stem (ES) cells through the intercrossing of p38alpha(+/-) mice. These ES cells were used to generate chimeric mice by RAG-deficient blastocyst complementation, with the lymphocytes in these mice being derived entirely from the ES cells. Surprisingly, B and T cell development were indistinguishable when comparing chimeric mice generated with p38alpha(+/+), p38alpha(+/-), and p38alpha(-/-) ES cell lines. Moreover, proliferation of p38alpha(-/-) B and T cells in response to Ag receptor and non-Ag receptor stimuli was intact. Thus, p38alpha is not an essential component of signaling pathways required for robust B and T lymphocyte developmental, nor is p38alpha essential for the proliferation of mature B and T cells.
- Published
- 2005
- Full Text
- View/download PDF
6. The B12/23 restriction is critically dependent on recombination signal nonamer and spacer sequences.
- Author
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Hughes MM, Tillman RE, Wehrly TD, White JM, and Sleckman BP
- Subjects
- 5' Untranslated Regions chemistry, 5' Untranslated Regions genetics, Animals, Antibody Diversity genetics, Base Sequence, CHO Cells, Cell Differentiation genetics, Cell Differentiation immunology, Cell Line, Cricetinae, DNA, Intergenic genetics, Extrachromosomal Inheritance genetics, Extrachromosomal Inheritance immunology, Gene Rearrangement, beta-Chain T-Cell Antigen Receptor, Genetic Markers, Immunoglobulin J-Chains genetics, Immunoglobulin Variable Region genetics, Mice, Mice, Transgenic, RNA Processing, Post-Transcriptional genetics, RNA Processing, Post-Transcriptional immunology, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, DNA, Intergenic chemistry, DNA-Binding Proteins genetics, Homeodomain Proteins genetics, Recombination, Genetic
- Abstract
Ag receptor variable region gene assembly is initiated through the formation of a synaptic complex which minimally includes the recombination-activating gene (RAG) 1/2 proteins and a pair of recombination signals (RSs) flanking the recombining gene segments. RSs are composed of conserved heptamer and nonamer sequences flanking relatively nonconserved spacers of 12 or 23 bp. RSs regulate variable region gene assembly within the context of the 12/23 rule which mandates that recombination only occurs between RSs of dissimilar spacer length. RSs can exert additional constraints on variable region gene assembly beyond imposing spacer length requirements. At a minimum this restriction, termed B12/23, is imposed on the Vbeta to DJbeta rearrangement step by the 5' Dbeta RS and is enforced at or before the DNA cleavage step of the V(D)J recombination reaction. In this study, the components of the 5' Dbeta RS required for enforcing the B12/23 rule are assessed on chromosomal substrates in vivo in the context of normal murine thymocyte development and on extrachromosomal substrates induced to undergo recombination in nonlymphoid cell lines. These analyses reveal that the integrity of the nonamer sequence as well as the highly conserved spacer nucleotides of the 5' Dbeta1 RS are critical for enforcing the B12/23 restriction. These findings have important implications for understanding the B12/23 restriction and the manner in which RS synaptic complexes are assembled in vivo.
- Published
- 2003
- Full Text
- View/download PDF
7. A threshold for central T cell tolerance to an inducible serum protein.
- Author
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Haribhai D, Engle D, Meyer M, Donermeyer D, White JM, and Williams CB
- Subjects
- Amino Acid Sequence, Animals, Autoantigens genetics, Autoantigens immunology, Cell Differentiation genetics, Cell Differentiation immunology, Clone Cells, Epitopes, T-Lymphocyte blood, Epitopes, T-Lymphocyte genetics, Epitopes, T-Lymphocyte immunology, Gene Expression Regulation immunology, Hemoglobins genetics, Hemoglobins immunology, Humans, Immunodominant Epitopes blood, Immunodominant Epitopes genetics, Immunodominant Epitopes immunology, Mice, Mice, Inbred AKR, Mice, Inbred C57BL, Mice, Transgenic, Molecular Sequence Data, Muramidase blood, Muramidase genetics, Muramidase immunology, Peptide Fragments blood, Peptide Fragments genetics, Peptide Fragments immunology, Recombinant Fusion Proteins immunology, Recombinant Fusion Proteins metabolism, Repressor Proteins genetics, Repressor Proteins immunology, T-Lymphocyte Subsets cytology, Tetracycline immunology, Thymus Gland cytology, Thymus Gland transplantation, Transgenes immunology, Transplantation Tolerance genetics, Autoantigens biosynthesis, Autoantigens blood, Recombinant Fusion Proteins biosynthesis, Recombinant Fusion Proteins blood, Self Tolerance genetics, T-Lymphocyte Subsets immunology
- Abstract
We report an inducible system of self Ag expression that examines the relationship between serum protein levels and central T cell tolerance. This transgenic approach is based on tetracycline-regulated expression of a secreted form of hen egg lysozyme, tagged with a murine hemoglobin (Hb) epitope. In the absence of the tetracycline-regulated transactivator, serum levels of the chimeric protein are extremely low (< or = 0.1 ng/ml) and the mice show partial tolerance to both Hb(64-76) and lysozyme epitopes. In the presence of the transactivator, expression increases to 1.5 ng/ml and the mice are completely tolerant. Partial tolerance was further investigated by crossing these mice to strains expressing transgenic TCRs. At the lowest Ag levels, 3.L2tg T cells (specific for Hb(64-76)/I-E(k)) escape the thymus and approximately 10% of CD4(+) splenocytes express the 3.L2 TCR. In contrast, 3A9 T cells (specific for hen egg lysozyme(46-61)/I-A(k)) are completely eliminated by negative selection. These data define a tolerogenic threshold for negative selection of Ag-specific T cells by circulating self proteins that are 100-fold more sensitive than previously demonstrated. They suggest that partial tolerance at extremely low levels of self Ag exposure is the result of a restricted repertoire of responding T cells, rather than a simple reduction in precursor frequency; tolerogenic thresholds are T cell specific.
- Published
- 2003
- Full Text
- View/download PDF
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