scholarly journals Use of somatic cell genetics to study chromosomes contributing to antigen plus I recognition by T cell hybridomas.

1983 ◽  
Vol 157 (2) ◽  
pp. 404-418 ◽  
Author(s):  
P Marrack ◽  
J Kappler
Keyword(s):  
T Cells ◽  
T Cell ◽  
Somatic Cell ◽  
Mouse Strain ◽  
Interleukin 2 ◽  
Antigen Presenting Cells ◽  
Keyhole Limpet Hemocyanin ◽  
Gene Products ◽  
Somatic Cell Genetics ◽  
Antigen Presenting

Keyhole limpet hemocyanin (KLH)/I region-specific T cell hybridomas have been prepared by fusing KLH/I-specific T cell blasts from mice with single pairs of metacentric chromosomes to the inducible, interleukin 2 (IL-2)-secreting T cell hybridoma FS6-14.13.AG2.1. T cell hybridomas with KLH/I receptors were identified by their ability to secrete IL-2 in response to KLH and the appropriate antigen-presenting cells. After cloning and subcloning, KLH/I reactivity was correlated with the presence or absence of metacentric chromosomes derived from the KLH/I-specific T cell blast parent. Hybridomas were identified that had lost all chromosomes 4 and 6 or 16 and 17 derived from their normal T cell parent, but retained the ability to respond to KLH/I. This suggested that products of genes on these chromosomes did not contribute to the specific portions of T cell Ag/I receptors. These gene products would include, of course, kappa and lambda chains and H-2. We did not obtain any T cell hybridomas that had lost both metacentric (8.12) chromosomes derived from T cells of the Robertsonian mouse strain Rb(8.12)5, so we could not draw any conclusions about the contributions of products of genes on these chromosomes. T cell hybridomas with KLH/I reactivity were found that contained only one metacentric (8.12) chromosome derived from this strain. Moreover, a T cell hybridoma was found that retained both metacentric (8.12) chromosomes from its normal T cell parent, but had lost KLH/I reactivity. These results suggested that neither two chromosomes 8 nor two chromosomes 12 were required for antigen/I reactivity in normal T cells and that antigen/I reactivity was controlled, at least in part, by genes mapping on chromosomes other than 8 or 12.

scholarly journals Antigen-reactive T clones. III. Low responder antigen-presenting cells function effectively to present antigen to selected T cell clones derived from (High Responder x Low Responder)F1 mice.

1981 ◽  
Vol 154 (3) ◽  
pp. 883-891 ◽  
Author(s):  
M Kimoto ◽  
T J Krenz ◽  
C G Fathman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presenting Cells ◽  
High Responder ◽  
Gene Products ◽  
T Cell Clones ◽  
Functional Capabilities ◽  
Cell Clones ◽  
Low Responder ◽  
Antigen Presenting

Long-term-cultured poly(Tyr, Glu)-poly-D,L,-Ala-poly-Lys [(T,G)-A--L]-reactive T cells and clones derived from (high responder x low responder)F1 [(C57BL/6 x A/J)F1] mice were shown to recognize (T,G)-A--L presented by cells from low responder strain A/J mice. The antigen-presenting determinant(s) that allowed recognition of (T,G)-A--L by such T cell clones was controlled by the I-A subregion of the major histocompatibility complex. These results suggest that there is no functional defect in the ability of low responder Ir gene products (I-A antigens) to associate with (T,G)-A--L for effective recognition by T cells. Although these results might tentatively be interpreted to suggest that Ir gene-controlled low responsiveness is due to the inability of the T cell to recognize the association between (T,G)-A--L and low responder I-A gene products, it is similarly possible that there might be a defect in the functional capabilities of low responder antigen-presenting cells to effectively process (T,G)-A--L into immunodominant epitopes.

scholarly journals Use of Leukemic Dendritic Cells for the Generation of Antileukemic Cellular Cytotoxicity Against Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia

Blood ◽  
1997 ◽  
Vol 89 (4) ◽  
pp. 1133-1142 ◽  
Author(s):  
Aniruddha Choudhury ◽  
James L. Gajewski ◽  
Jan C. Liang ◽  
Uday Popat ◽  
David F. Claxton ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cytotoxic Activity ◽  
Chronic Myelogenous Leukemia ◽  
Interleukin 2 ◽  
Antigen Presenting Cells ◽  
Myelogenous Leukemia ◽  
Antigen Presenting

Abstract The success of adoptive immunotherapy for the treatment of leukemia depends on the generation of T cells that can specifically react with malignant cells. Dendritic cells (DCs) are important antigen-presenting cells in the development of antileukemic T-cell responses. In this study, we generated DCs from peripheral blood cells of patients with chronic myelogenous leukemia (CML). CML cells incubated concurrently with granulocyte-macrophage colony-stimulating factor, interleukin-4, and tumor necrosis factor-α in vitro developed morphologic and phenotypic characteristics of DCs. Fluorescence in situ hybridization showed the presence of t(9; 22) in the nuclei of these cells, indicating that they were leukemic in origin. These cells were potent stimulators of lymphocyte proliferation in specific in vitro assays for DC function. Autologous T cells stimulated with in vitro-generated, leukemic DCs displayed vigorous cytotoxic activity against CML cells but low reactivity to major histocompatability complex-matched normal bone marrow cells. Cytotoxic activity against CML targets was fourfold to sixfold higher using DC-stimulated autologous T cells than with autologous T cells expanded by culture with interleukin-2 alone. DC-stimulated T cells also inhibited growth of CML clonogenic precursors in colony-forming assays in vitro. These results suggest that cytokine-driven in vitro differentiation of CML cells results in generation of DCs with potent T-cell stimulatory function. In vitro-generated DCs can be effectively used as antigen-presenting cells for the ex vivo expansion of antileukemic T cells.

scholarly journals Development of Stable Chimeric IL-15 for Trans-Presentation by the Antigen Presenting Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Manoj Patidar ◽  
Naveen Yadav ◽  
Sarat K. Dalai
Keyword(s):  
T Cells ◽  
T Cell ◽  
Half Life ◽  
Therapeutic Potential ◽  
Chimeric Protein ◽  
Antigen Presenting Cells ◽  
T Cell Response ◽  
Antigen Presenting

IL-15 is one of the important biologics considered for vaccine adjuvant and treatment of cancer. However, a short half-life and poor bioavailability limit its therapeutic potential. Herein, we have structured IL-15 into a chimeric protein to improve its half-life enabling greater bioavailability for longer periods. We have covalently linked IL-15 with IgG2 base to make the IL-15 a stable chimeric protein, which also increased its serum half-life by 40 fold. The dimeric structure of this kind of IgG based biologics has greater stability, resistance to proteolytic cleavage, and less frequent dosing schedule with minimum dosage for achieving the desired response compared to that of their monomeric forms. The structured chimeric IL-15 naturally forms a dimer, and retains its affinity for binding to its receptor, IL-15Rβ. Moreover, with the focused action of the structured chimeric IL-15, antigen-presenting cells (APC) would transpresent chimeric IL-15 along with antigen to the T cell, that will help the generation of quantitatively and qualitatively better antigen-specific memory T cells. In vitro and in vivo studies demonstrate the biological activity of chimeric IL-15 with respect to its ability to induce IL-15 signaling and modulating CD8+ T cell response in favor of memory generation. Thus, a longer half-life, dimeric nature, and anticipated focused transpresentation by APCs to the T cells will make chimeric IL-15 a super-agonist for memory CD8+ T cell responses.

Abstract 252: Interleukin-27 Signaling Regulates Myeloid Cells Activation in Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Iuliia Peshkova ◽  
Aliia Fatkhullina ◽  
Ekaterina Koltsova
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
Antigen Presenting Cells ◽  
Atherosclerotic Lesions ◽  
Mediators Of Inflammation ◽  
Antigen Presenting ◽  
Deficient Mice ◽  
Pro Inflammatory Cytokines

Atherosclerosis is a lipid-driven inflammatory disease characterized by the progressive plaque growth in the vessels. Cytokines are important mediators of inflammation and atherosclerosis. While pro-inflammatory cytokines were extensively investigated, little is known about the role of anti-inflammatory cytokines as to their ability to control vascular inflammation. We tested whether immunoregulatory IL-27R signaling is important to control inflammation in mouse models of atherosclerosis. We found that atherosclerosis-prone mice with hematopoietic deficiency of IL-27R ( Ldlr -/- mice reconstituted with bone marrow from Il27ra -/- ) or global deficiency ( Il27ra -/- x Apoe -/- ) developed significantly larger atherosclerotic lesions compared to controls. Atherosclerotic lesions in IL-27R deficient mice contained more CD45 + leukocytes and CD4 + T cells, which produced pro-atherogenic cytokines IL-17A and TNF-α. These cytokines normally suppressed by IL-27, regulated the expression of CCL2 and other chemokines, which in turn led to accumulation of myeloid CD11b + and CD11c + cells in atherosclerotic aortas. Using two-photon microscopy, we found enhanced interactions between antigen presenting cells and T cells in the aortas of IL-27R deficient mice accompanied by enhanced CD4 T cell proliferation. Moreover, macrophages in Il27ra -/- aortas also demonstrated enhanced ability to produce pro-inflammatory cytokines, including IL-1. The blockade of IL-1R signaling, however, strongly suppressed atherosclerosis progression in IL-27R deficient but not control mice, suggesting an important role of IL-27 in the regulation of IL-1 production in atherosclerosis. Overall, our data demonstrate that IL-27R signaling in atherosclerosis is required to control function of antigen presenting cells modulating subsequent T cell activation in the aortas. Moreover, it controls macrophage activation and pro-inflammatory myeloid cell-derived cytokine production. These mechanisms altogether curb pathogenic T cell lineage differentiation and, thus, atherosclerosis, suggesting potent anti-atherogenic role of IL-27.

scholarly journals Antigen-specific T cell clones restricted to unique F(1) major histocompatibility complex determinants. Inhibition of proliferation with a monoclonal anti-Ia antibody

1981 ◽  
Vol 153 (3) ◽  
pp. 677-693 ◽  
Author(s):  
B Sredni ◽  
LA Matis ◽  
EA Lerner ◽  
WE Paul ◽  
RH Schwartz
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Proliferative Response ◽  
Cell Populations ◽  
Gene Products ◽  
Spleen Cells ◽  
Histocompatibility Complex ◽  
Cell Clones ◽  
Antigen Presenting

The existence of T cells specific for soluble antigens in association with unique F(1) or recombinant major histocompatibility complex (MHC) gene products was first postulated from studies on the proliferative response of whole T cell populations to the antigen poly(Glu(55)Lys(36)Phe(9))(n) (GLφ). In this paper we use the newly developed technology of T lymphocyte cloning to establish unequivocally the existence of such cells specific for GLφ and to generalize their existence by showing that F(1)- specific cells can be isolated from T cell populations primed to poly(Glu(60)Ala(30)Tyr(10))(n) (GAT) where such clones represent only a minor subpopulation of cells. Gl.4b-primed B10.A(5R) and GAT-primed (B10.A × B10)F(1) lymph node T cells were cloned in soft agar, and the colonies that developed were picked and expanded in liquid culture. The GLφ-specific T cells were then recloned under conditions of high-plating efficiency to ensure that the final colonies originated from single cells. T cells from such rigorously cloned populations responded to stimulation with GILφ but only in the presence of nonimmune, irradiated spleen cells bearing (B10.A × B10)F(1) or the syngeneic B 10.A(5R) recombinant MHC haplotype. Spleen cells from either the B10 or B 10.A parental strains failed to support a proliferative response, even when added together. (B10 × B10.D2)F(1) and (B10 × B10.RIII)F(1) spleen cells also supported a proliferative response but (B10 × B10.Q)F(1) and (B10 X B10.S)F(1) spleen cells did not. These results suggested that the T cell clones were specific for GL[phi} in association with the β(AE)(b)-α(E) (k,d,r,) Ia molecule and that recognition required both gene products to be expressed in the same antigen-presenting cells. Support for this interpretation was obtained from inhibition experiments using the monoclonal antibody Y-17 specific for a determinant on the β(AE)(b)-αE Ia molecule. Y-17 completely inhibited the proliferative response of a GLφ-specific clone but had no effect on the response of either a PPD-specific or GAT-specific clone, both of which required the β(A)-α(A) Ia molecule as their restriction element. No evidence could be found for the involvement of suppressor T cells in this inhibition. We therefore conclude that the phenomenon of F(1)-restricted recognition by proliferating T cells results from the presence of antigen- specific clones that must recognize unique F(1) or recombinant Ia molecules on the surface of antigen-presenting cells in addition to antigen in order to be stimulated.

scholarly journals Distinct Roles of α7 nAChRs in Antigen-Presenting Cells and CD4+ T Cells in the Regulation of T Cell Differentiation

2019 ◽  
Vol 10 ◽  
Author(s):  
Masato Mashimo ◽  
Masayo Komori ◽  
Yuriko Y. Matsui ◽  
Mami X. Murase ◽  
Takeshi Fujii ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cd4 T Cells ◽  
Antigen Presenting Cells ◽  
T Cell Differentiation ◽  
Antigen Presenting ◽  
Α7 Nachrs

scholarly journals Abortive Proliferation of Rare T Cells Induced by Direct or Indirect Antigen Presentation by Rare B Cells In Vivo

1998 ◽  
Vol 187 (10) ◽  
pp. 1611-1621 ◽  
Author(s):  
Sarah E. Townsend ◽  
Christopher C. Goodnow
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Antigen Presentation ◽  
Cell Fate ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antigen Presenting Cells ◽  
Antigen Presenting

Antigen-specific B cells are implicated as antigen-presenting cells in memory and tolerance responses because they capture antigens efficiently and localize to T cell zones after antigen capture. It has not been possible, however, to visualize the effect of specific B cells on specific CD4+ helper T cells under physiological conditions. We demonstrate here that rare T cells are activated in vivo by minute quantities of antigen captured by antigen-specific B cells. Antigen-activated B cells are helped under these conditions, whereas antigen-tolerant B cells are killed. The T cells proliferate and then disappear regardless of whether the B cells are activated or tolerant. We show genetically that T cell activation, proliferation, and disappearance can be mediated either by transfer of antigen from antigen-specific B cells to endogenous antigen-presenting cells or by direct B–T cell interactions. These results identify a novel antigen presentation route, and demonstrate that B cell presentation of antigen has profound effects on T cell fate that could not be predicted from in vitro studies.

scholarly journals CD4+ T-cell killing of multiple myeloma cells is mediated by resident bone marrow macrophages

2020 ◽  
Vol 4 (12) ◽  
pp. 2595-2605 ◽  
Author(s):  
Ole Audun W. Haabeth ◽  
Kjartan Hennig ◽  
Marte Fauskanger ◽  
Geir Åge Løset ◽  
Bjarne Bogen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Antigen Presenting Cells ◽  
Bone Marrow Microenvironment ◽  
Cd4 T Cell ◽  
Myeloma Cells ◽  
Antigen Presenting

Abstract CD4+ T cells may induce potent antitumor immune responses through interaction with antigen-presenting cells within the tumor microenvironment. Using a murine model of multiple myeloma, we demonstrated that adoptive transfer of idiotype-specific CD4+ T cells may elicit curative responses against established multifocal myeloma in bone marrow. This finding indicates that the myeloma bone marrow niche contains antigen-presenting cells that may be rendered tumoricidal. Given the complexity of the bone marrow microenvironment, the mechanistic basis of such immunotherapeutic responses is not known. Through a functional characterization of antitumor CD4+ T-cell responses within the bone marrow microenvironment, we found that killing of myeloma cells is orchestrated by a population of bone marrow–resident CD11b+F4/80+MHC-IIHigh macrophages that have taken up and present secreted myeloma protein. The present results demonstrate the potential of resident macrophages as powerful mediators of tumor killing within the bone marrow and provide a basis for novel therapeutic strategies against multiple myeloma and other malignancies that affect the bone marrow.

scholarly journals Dendritic cells are potent antigen-presenting cells for microbial superantigens.

1992 ◽  
Vol 175 (1) ◽  
pp. 267-273 ◽  
Author(s):  
N Bhardwaj ◽  
S M Friedman ◽  
B C Cole ◽  
A J Nisanian
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Antigen Presenting Cells ◽  
Small Subset ◽  
Cell Functions ◽  
Cell Responses ◽  
Antigen Presenting

Dendritic cells are a small subset of human blood mononuclear cells that are potent stimulators of several T cell functions. Here we show they are 10-50-fold more potent than monocytes or B cells in inducing T cell responses to a panel of superantigens. Furthermore, dendritic cells can present femtomolar concentrations of superantigen to T cells even at numbers where other antigen-presenting cells (APCs) are inactive. Although dendritic cells express very high levels of the major histocompatibility complex products that are required to present superantigens, it is only necessary to pulse these APCs for 1 hour with picomolar levels of one superantigen, staphylococcal enterotoxin B, to maximally activate T cells. Our results suggest that very small amounts of superantigen will be immunogenic in vivo if presented on dendritic cells.

Immunotherapy of Hematologic Malignancy

Hematology ◽  
2003 ◽  
Vol 2003 (1) ◽  
pp. 331-349 ◽  
Author(s):  
Helen E. Heslop ◽  
Freda K. Stevenson ◽  
Jeffrey J. Molldrem
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Experience ◽  
Viral Vectors ◽  
Hematologic Malignancy ◽  
Antigen Presenting Cells ◽  
Hematologic Malignancies ◽  
Peptide Vaccines ◽  
Antigen Presenting

Abstract Over the past few years, improved understanding of the molecular basis of interactions between antigen presenting cells and effector cells and advances in informatics have both led to the identification of many candidate antigens that are targets for immunotherapy. However, while immunotherapy has successfully eradicated relapsed hematologic malignancy after allogeneic transplant as well as virally induced tumors, limitations have been identified in extending immunotherapy to a wider range of hematologic malignancies. This review provides an overview of three immunotherapy strategies and how they may be improved. In Section I, Dr. Stevenson reviews the clinical experience with genetic vaccines delivered through naked DNA alone or viral vectors, which are showing promise in clinical trials in lymphoma and myeloma patients. She describes efforts to manipulate constructs genetically to enhance immunogenicity and to add additional elements to generate a more sustained immune response. In Section II, Dr. Molldrem describes clinical experience with peptide vaccines, with a particular focus on myeloid tissue-restricted proteins as GVL target antigens in CML and AML. Proteinase 3 and other azurophil granule proteins may be particularly good targets for both autologous and allogeneic T-cell responses. The potency of peptide vaccines may potentially be increased by genetically modifying peptides to enhance T-cell receptor affinity. Finally, in Section III, Dr. Heslop reviews clinical experience with adoptive immunotherapy with T cells. Transferred T cells have clinical benefit in treating relapsed malignancy post transplant, and Epstein-Barr virus associated tumors. However, T cells have been less successful in treating other hematologic malignancies due to inadequate persistence or expansion of adoptively transferred cells and the presence of tumor evasion mechanisms. An improved understanding of the interactions of antigen presenting cells with T cells should optimize efforts to manufacture effector T cells, while manipulation of lymphocyte homeostasis in vivo and development of gene therapy approaches may enhance the persistence and function of adoptively transferred T cells.

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