scholarly journals A major histocompatibility complex class II restriction for BioBreeding/Worcester diabetes-inducing T cells.

1995 ◽  
Vol 182 (4) ◽  
pp. 923-930 ◽  
Author(s):  
K E Ellerman ◽  
A A Like
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Insulin Dependent Diabetes Mellitus ◽  
Class Ii ◽  
Class I ◽  
Dependent Diabetes Mellitus ◽  
Insulin Dependent ◽  
T Cell Lines

Inbred diabetes-prone (DP) BioBreeding/Worcester (BB/Wor) (RT1u) rats develop spontaneous autoimmune diabetes, which, like human insulin-dependent diabetes mellitus, is mediated by autoreactive T lymphocytes. Breeding studies have shown an absolute requirement for at least one copy of the major histocompatibility complex (MHC) RT1u haplotype for spontaneous diabetes expression. Concanavalin A-activated spleen cells from acutely diabetic DP rats adoptively transfer diabetes only to recipients that express at least one RT1u haplotype. To investigate the basis for the MHC requirement in BB/Wor autoimmunity, diabetes-inducing T cell lines were derived from the spleens of acutely diabetic DP rats. Upon activation in vitro with islet cells, the T cell lines adoptively transfer insulitis and diabetes into young DP recipients and non-diabetes-prone RT1 congenic rat strains that are class IIu. Recipients that are RT1u at only the class I A or C locus, but not at the class II B/D loci, do not develop diabetes after T cell transfer. The adoptive transfer of diabetes by Concanavalin A-activated diabetic DP spleen cells also requires that donor and recipient share class II B/Du gene products. Furthermore, the adoptive transfer of diabetes into MHC class IIu congenic rats is independent of the class I haplotype; i.e., it occurs in the presence of class I Aa Cu or Au Ca gene products. BB/Wor T cells can be activated in vitro for the transfer of diabetes with islet cell antigens and class II-positive but not class IIu-negative antigen-presenting cells. The inductive phase of BB diabetes is therefore MHC class II restricted, and this appears to operate at the level of interaction between inducing T cells and class IIu antigen-presenting cells. These results may explain the well-documented, but not yet understood, MHC class II genetic contribution to insulin-dependent diabetes mellitus pathogenesis, and they may facilitate the development of protocols designed to prevent diabetes onset in susceptible individuals.

Double Loading of Dendritic Cell MHC Class I and MHC Class II with an AML Antigen Repertoire Enhances Primary and Secondary T-Cell Responses In Vitro.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2529-2529
Author(s):  
William K. Decker ◽  
Dongxia Xing ◽  
Sufang Li ◽  
Simon N. Robinson ◽  
Hong Yang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd8 T Cells ◽  
Class Ii ◽  
T Cell Response ◽  
Class I ◽  
Cross Presentation ◽  
Ifn Γ

Abstract Despite improvements in therapy for acute myelogenous leukemia (AML), a significant percentage of patients still relapse and succumb to their disease. Dendritic cell immunotherapy offers the promise of potentially effective supportive therapy for a variety of neoplastic conditions; and the use of DCs loaded with tumor antigens is now recognized as an important investigational therapy. Though a variety of methods have been used to load DC vaccines, the loading of the MHC class II compartment with tumor lysate has predominated. The priming of a class II-mediated (CD4) T-cell response may be crucial to the success of DC immunotherapy as such a response is likely required for the development of memory CD8+ T-cells. DC cross-presentation is credited with the ability of lysate-loaded DCs to prime both CD4 and CD8 T-cell responses, enabling the generation of CD8+ CTLs without the loading of the MHC class I compartment (i.e. the cytoplasm). Recently, however, several reports have raised doubts as to the efficiency of cross-presentation as a mechanism for CTL priming in vivo. To examine this issue, we have loaded human DCs with both AML tumor lysate and mRNA. This technique allows the full repertoire of class I antigens to be presented without dependence upon cross-presentation; and, moreover, provides a full complement of class II antigens necessary for CD4 T-cell priming and the generation of memory responses. Methods: CD14+ precursors were isolated from normal donor PBPCs by magnetic separation. Immature DCs were then generated by culturing precursors for six days in GM-CSF and IL-4. Lysate was produced by three successive freeze/thaw cycles of blasts. mRNA was extracted from blasts using Trizol and oligo-dT separation. Immature DCs were pulsed for three hours with AML lysate and subsequently electroporated with AML mRNA. Loaded DCs were matured for 48 hours with IL-1β, TNF-α, IL-6, and PGE2 and then used to prime autologous T-cells. Short-term responses were assayed on day 5 of the 1st stimulation. Memory responses were assayed on day 10 of a tertiary stimulation. Results: Doubly-loaded DCs can prime a superior T-cell response in vitro in comparison to that of singly-loaded DCs, demonstrating a 30–70% increase in IFN-γ ELISpots over lysate-loaded DCs (p<0.001) and a 3–4 fold increase in ELISpots in comparison to mRNA loaded DCs (p<0.001). These results were verified by flow cytometry which showed 35% of CD8+ T-cells primed by doubly-loaded DCs were CD69+/IFN-γ+ vs. 14% of CD8+ T-cells primed by lysate-loaded DCs (p<0.001). This enhancement may be based upon both an upregulation of CD83 surface expression (p<0.0019) of doubly-loaded DCs and/or the upregulation of B7.1/B7.2 that accompanies elevated CD40L signaling. Memory responses were also greatly improved, with a 126% increase in total ELISpots (double loaded DCs versus lysate loaded DCs; p<0.03) and a 187% increase in total IFN-γ secretion (p<0.03). Unloaded (p<0.01) and mRNA (p<0.007) loaded DCs exhibited a virtual inability to generate memory T-cells in vitro, suggesting that the perpetuation of the memory response is reliant upon T-cell help. Conclusion: DCs doubly-loaded with lysate and mRNA are more efficient in the generation of primary and secondary immune responses than are singly-loaded DCs. The clinical administration of such doubly-loaded DCs may offer an important therapeutic option to patients with AML.

CD4 function in thymocyte differentiation and T cell activation

1993 ◽  
Vol 342 (1299) ◽  
pp. 25-34 ◽  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Subset ◽  
Class Ii ◽  
Class I ◽  
Double Positive

The ectodomains of the T cell surface glycoproteins CD4 and CD8 bind to membrane-proximal domains of MHC class II and class I molecules, respectively, while both cytoplasmic domains interact with the protein tyrosine kinase (PTK) p56 lck (lck) through a shared cysteine-containing motif. Function of CD4 and CD8 requires their binding to the same MHC molecule as that recognized by the T cell antigen receptor (TCR). In vitro studies indicate that CD4-associated lck functions even in the absence of kinase activity. In vivo experiments show that, whereas helper T cell development is impaired in CD4-deficient mice, high level expression of a transgenic CD4 that cannot bind lck rescues development of this T cell subset. These studies suggest that CD4 is an adhesion molecule whose localization is regulated through protein-protein interactions of the associated PTK and whose function is to increase the stability of the TCR signalling complex by binding to the relevant MHC. The function of CD4 in development has been further studied in the context of how double positive (CD4+ CD8+ ) thymocytes mature into either CD4 + T cells with helper function and TCR specificity for class II or into CD8 + T cells with cytotoxic function and specificity for class I. Studies using CD4- transgenic mice indicate that development of single positive T cells involves stochastic downregulation of either CD4 or CD8, coupled to activation of a cytotoxic or helper program, respectively, and subsequent selection based on the ability of the TCR and remaining coreceptor to engage the same MHC molecule.

scholarly journals Nonmalignant T cells stimulate growth of T-cell lymphoma cells in the presence of bacterial toxins

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3325-3332 ◽  
Author(s):  
Anders Woetmann ◽  
Paola Lovato ◽  
Karsten W. Eriksen ◽  
Thorbjørn Krejsgaard ◽  
Tord Labuda ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Mhc Class Ii ◽  
Interleukin 2 ◽  
Class Ii ◽  
Bacterial Toxins ◽  
Dependent Manner ◽  
Malignant Cells ◽  
T Cell Lines

AbstractBacterial toxins including staphylococcal enterotoxins (SEs) have been implicated in the pathogenesis of cutaneous T-cell lymphomas (CTCLs). Here, we investigate SE-mediated interactions between nonmalignant T cells and malignant T-cell lines established from skin and blood of CTCL patients. The malignant CTCL cells express MHC class II molecules that are high-affinity receptors for SE. Although treatment with SE has no direct effect on the growth of the malignant CTCL cells, the SE-treated CTCL cells induce vigorous proliferation of the SE-responsive nonmalignant T cells. In turn, the nonmalignant T cells enhance proliferation of the malignant cells in an SE- and MHC class II–dependent manner. Furthermore, SE and, in addition, alloantigen presentation by malignant CTCL cells to irradiated nonmalignant CD4+ T-cell lines also enhance proliferation of the malignant cells. The growth-promoting effect depends on direct cell-cell contact and soluble factors such as interleukin-2. In conclusion, we demonstrate that SE triggers a bidirectional cross talk between nonmalignant T cells and malignant CTCL cells that promotes growth of the malignant cells. This represents a novel mechanism by which infections with SE-producing bacteria may contribute to pathogenesis of CTCL.

scholarly journals A Class II-Restricted CD8γ13 T-Cell Clone Protects During Chlamydia muridarum Genital Tract Infection

2020 ◽  
Vol 221 (11) ◽  
pp. 1895-1906
Author(s):  
Raymond M Johnson ◽  
Norma Olivares-Strank ◽  
Gang Peng
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd8 T Cells ◽  
Genital Tract ◽  
Cell Clone ◽  
Class Ii ◽  
Class I ◽  
T Cell Clone ◽  
Tract Infections

Abstract Background The T-cell response to chlamydia genital tract infections in humans and mice is unusual because the majority of antigen-specific CD8 T cells are not class I restricted (referred to here as “unrestricted” or “atypical”). We previously reported that a subset of unrestricted murine chlamydia-specific CD8 T cells had a cytokine polarization pattern that included interferon (IFN)-γ and interleukin (IL)-13. Methods In this study, we investigated the transcriptome of CD8γ13 T cells, comparing them to Tc1 clones using microarray analysis. That study revealed that CD8γ13 polarization included IL-5 in addition to IFN-γ and IL-13. Adoptive transfer studies were performed with Tc1 clones and a CD8γ13 T-cell clone to determine whether either influenced bacterial clearance or immunopathology during Chlamydia muridarum genital tract infections. Results To our surprise, an adoptively transferred CD8γ13 T-cell clone was remarkably proficient at preventing chlamydia immunopathology, whereas the multifunctional Tc1 clone did not enhance clearance or significantly alter immunopathology. Mapping studies with major histocompatibility complex (MHC) class I- and class II-deficient splenocytes showed our previously published chlamydia-specific CD8 T-cell clones are MHC class II restricted. Conclusions The MHC class II-restricted CD8 T cells may play an important role in protection from intracellular pathogens that limit class I antigen presentation or diminish CD4 T-cell numbers or impair their function.

Human T Cells with Distinct Specificities Mediate Graft-Versus-Leukemia Reactivity and Xenogeneic Graft-Versus-Host Disease in a NOD/Scid Mouse Model for Human Acute Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1330-1330
Author(s):  
Sanja Stevanovic ◽  
Bart Nijmeijer ◽  
Marianke LJ Van Schie ◽  
Roelof Willemze ◽  
Marieke Griffioen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Class I ◽  
T Cell Clones ◽  
Cell Clones ◽  
Human T Cells

Abstract Abstract 1330 Poster Board I-352 Immunodeficient mice inoculated with human leukemia can be used as a model to investigate Graft-versus-Leukemia (GvL) effects of donor lymphocyte infusions (DLIs). In addition to GvL reactivity, treatment with DLI induces xenogeneic Graft-versus-Host Disease (GvHD) in mice, characterized by pancytopenia and weight loss. In patients treated with DLI for relapsed or residual leukemia after allogeneic stem cell transplantation, immune responses against non-leukemic cells may also cause GvHD. It has been suggested that GvL reactivity and GvHD, which co-develop in vivo, can be separated and that distinct T cells exist with the specific capacity to mediate GvL reactivity or GvHD. Since adoptive T cell transfer models that allow analysis of separation of GvL and GvHD are rare, we aimed to establish whether GvL reactivity and xenogeneic GvHD could be separated using our model of human leukemia-engrafted NOD/scid mouse after treatment with human donor T cells. In this study, non-conditioned NOD/scid mice engrafted with primary human acute lymphoblastic leukemic cells were treated with CD3+ DLI. Established tumors were effectively eliminated by emerging human T cells, but also induced xenogeneic GvHD. Flowcytometric analysis demonstrated that the majority of emerging CD8+ and CD4+ T cells were activated (HLA-DR+) and expressed an effector memory phenotype (CD45RA-CD45RO+CCR7-). To investigate whether GvL reactivity and xenogeneic GvHD were mediated by the same T cells showing reactivity against both human leukemic and murine cells, or displaying distinct reactivity against human leukemic and murine cells, we clonally isolated and characterized the T cells during the GvL response and xenogeneic GvHD. T cell clones were analyzed for reactivity against primary human leukemic cells and primary NOD/scid hematopoietic (BM and spleen cells) and non-hematopoietic (skin fibroblasts) cells in IFN-g ELISA. Isolated CD8+ and CD4+ T cell clones were shown to recognize either human leukemic or murine cells, indicating that GvL response and xenogeneic GvHD were mediated by different human T cells. Flowcytometric analysis demonstrated that all BM and spleen cells expressed MHC class I, whereas only 1-3 % of the cells were MHC class II +. Primary skin fibroblasts displayed low MHC class I and completely lacked MHC class II expression. Xeno-reactive CD8+ T cell clones were shown to recognize all MHC class I + target cells and xeno-reactive CD4+ T cells clones displayed reactivity only against MHC class II + target cells. To determine the MHC restriction of xeno-reactive T cell clones, NOD/scid bone marrow (BM) derived dendritic cells (DC) expressing high levels of murine MHC class I and class II were tested for T cell recognition in the presence or absence of murine MHC class I and class II monoclonal antibodies in IFN-g ELISA. Xeno-reactive CD8+ T cell clones were shown to be MHC class I (H-2Kd or H-2Db) restricted, whereas xeno-reactive CD4+ T cell clones were MHC class II (I-Ag7) restricted, indicating that xeno-reactivity reflects genuine human T cell response directed against allo-antigens present on murine cells. Despite production of high levels of IFN-gamma, xeno-reactive CD8+ and CD4+ T cell clones failed to exert cytolytic activity against murine DC, as determined in a 51Cr-release cytotoxicity assay. Absence of cytolysis by CD8+ T cell clones, which are generally considered as potent effector cells, may be explained by low avidity interaction between human T cells and murine DC, since flowcytometric analysis revealed sub-optimal activation of T cells as measured by CD137 expression and T cell receptor downregulation upon co-culture with murine DC, and therefore these results indicate that xenogeneic GvHD in this model is likely to be mediated by cytokines. In conclusion, in leukemia-engrafted NOD/scid mice treated with CD3+ DLI, we show that GvL reactivity and xenogeneic GvHD are mediated by separate human T cells with distinct specificities. All xeno-reactive T cell clones showed genuine recognition of MHC class I or class II associated allo-antigens on murine cells similar as GvHD-inducing human T cells. These data suggest that our NOD/scid mouse model of human acute leukemia may be valuable for studying the effectiveness and specificity of selectively enriched or depleted T cells for adoptive immunotherapy. Disclosures: No relevant conflicts of interest to declare.

Sialoadhesin-Positive Host Macrophages Play an Essential Role in Graft-Versus-Leukemia Reactivity in Mice

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4375-4386 ◽  
Author(s):  
Susanne Müerköster ◽  
Marian Rocha ◽  
Paul R. Crocker ◽  
Volker Schirrmacher ◽  
Victor Umansky
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Cd8 T Cells ◽  
Class I ◽  
Peptide Epitope ◽  
Peptide Epitopes ◽  
Graft Versus Leukemia

We recently established an effective immune T-cell–mediated graft-versus-leukemia (GVL) murine model system in which complete tumor remissions were achievable even in advanced metastasized cancer. We now describe that this T-cell–mediated therapy is dependent on host macrophages expressing the lymphocyte adhesion molecule sialoadhesin (Sn). Depletion of Kupffer cells in tumor-bearing mice during adoptive immunotherapy (ADI) or the treatment of these animals with anti-Sn monoclonal antibodies led to complete or partial inhibition of the immune T-cell–mediated therapeutic effect. Furthermore, Sn+ host macrophages in livers formed clusters during ADI with donor CD8 T cells. To test for a possible antigen presentation function of these macrophages, we used as an in vitro model the antigen β-galactosidase for which a dominant major histocompatibility complex (MHC) class I Ld-restricted peptide epitope is known to be recognized by specific CD8 cytotoxic T lymphocytes (CTL). We demonstrate that purified Sn+ macrophages can process exogenous β-galactosidase and stimulate MHC class I peptide-restricted CTL responses. Thus, Sn+ macrophages, which are significantly increased in the liver after ADI, may process tumor-derived proteins via the MHC class I pathway as well as via the MHC class II pathway, as shown previously, and present respective peptide epitopes to CD8 as well as to CD4 immune T cells, respectively. The synergistic interactions observed before between immune CD4 and CD8 T cells during ADI could thus occur in the observed clusters with Sn+ host macrophages.

scholarly journals Genetic Dissection of Primary and Secondary Responses to a Widespread Natural Pathogen of the Gut,Eimeria vermiformis

2000 ◽  
Vol 68 (11) ◽  
pp. 6273-6280 ◽  
Author(s):  
Adrian L. Smith ◽  
Adrian C. Hayday
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Primary Response ◽  
Class I ◽  
Class Ii Mhc ◽  
Ifn Γ ◽  
Αβ T Cells

ABSTRACT Because most pathogens initially challenge the body at epithelial surfaces, it is important to dissect the mechanisms that underlie T-cell responses to infected epithelial cells in vivo. The coccidian parasites of the genus Eimeria are protozoan gut pathogens that elicit a potent, protective immune response in a wide range of host species. CD4+ αβ T cells and gamma interferon (IFN-γ) are centrally implicated in the primary immunoprotective response. To define any additional requirements for the primary response and to develop a comparison between the primary and the secondary response, we have studied Eimeria infections of a broad range of genetically altered mice. We find that a full-strength primary response depends on β2-microglobulin (class I major histocompatibility complex [MHC] and class II MHC and on IFN-γ and interleukin-6 (IL-6) but not on TAP1, perforin, IL-4, Fas ligand, or inducible nitric oxide synthetase. Indeed, MHC class II-deficient and IFN-γ-deficient mice are as susceptible to primary infection as mice deficient in all αβ T cells. Strikingly, the requirements for a highly effective αβ-T-cell-driven memory response are less stringent, requiring neither IFN-γ nor IL-6 nor class I MHC. The class II MHC dependence was also reduced, with adoptively transferable immunity developing in MHC class II−/− mice. Besides the improved depiction of an immune response to a natural gut pathogen, the finding that effective memory can be elicited in the absence of primary effector responses appears to create latitude in the design of vaccine strategies.

Sialoadhesin-Positive Host Macrophages Play an Essential Role in Graft-Versus-Leukemia Reactivity in Mice

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4375-4386 ◽  
Author(s):  
Susanne Müerköster ◽  
Marian Rocha ◽  
Paul R. Crocker ◽  
Volker Schirrmacher ◽  
Victor Umansky
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Cd8 T Cells ◽  
Class I ◽  
Peptide Epitope ◽  
Peptide Epitopes ◽  
Graft Versus Leukemia

Abstract We recently established an effective immune T-cell–mediated graft-versus-leukemia (GVL) murine model system in which complete tumor remissions were achievable even in advanced metastasized cancer. We now describe that this T-cell–mediated therapy is dependent on host macrophages expressing the lymphocyte adhesion molecule sialoadhesin (Sn). Depletion of Kupffer cells in tumor-bearing mice during adoptive immunotherapy (ADI) or the treatment of these animals with anti-Sn monoclonal antibodies led to complete or partial inhibition of the immune T-cell–mediated therapeutic effect. Furthermore, Sn+ host macrophages in livers formed clusters during ADI with donor CD8 T cells. To test for a possible antigen presentation function of these macrophages, we used as an in vitro model the antigen β-galactosidase for which a dominant major histocompatibility complex (MHC) class I Ld-restricted peptide epitope is known to be recognized by specific CD8 cytotoxic T lymphocytes (CTL). We demonstrate that purified Sn+ macrophages can process exogenous β-galactosidase and stimulate MHC class I peptide-restricted CTL responses. Thus, Sn+ macrophages, which are significantly increased in the liver after ADI, may process tumor-derived proteins via the MHC class I pathway as well as via the MHC class II pathway, as shown previously, and present respective peptide epitopes to CD8 as well as to CD4 immune T cells, respectively. The synergistic interactions observed before between immune CD4 and CD8 T cells during ADI could thus occur in the observed clusters with Sn+ host macrophages.

scholarly journals Neoleukin-2 enhances anti-tumour immunity downstream of peptide vaccination targeted by an anti-MHC class II VHH

Open Biology ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 190235 ◽  
Author(s):  
Stephanie J. Crowley ◽  
Patrick T. Bruck ◽  
Md Aladdin Bhuiyan ◽  
Amelia Mitchell-Gears ◽  
Michael J. Walsh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Class Ii ◽  
Tumour Immunity ◽  
Tumour Rejection

Cancer-specific mutations can lead to peptides of unique sequence presented on MHC class I to CD8 T cells. These neoantigens can be potent tumour-rejection antigens, appear to be the driving force behind responsiveness to anti-CTLA-4 and anti-PD1/L1-based therapies and have been used to develop personalized vaccines. The platform for delivering neoantigen-based vaccines has varied, and further optimization of both platform and adjuvant will be necessary to achieve scalable vaccine products that are therapeutically effective at a reasonable cost. Here, we developed a platform for testing potential CD8 T cell tumour vaccine candidates. We used a high-affinity alpaca-derived VHH against MHC class II to deliver peptides to professional antigen-presenting cells. We show in vitro and in vivo that peptides derived from the model antigen ovalbumin are better able to activate naive ovalbumin-specific CD8 T cells when conjugated to an MHC class II-specific VHH when compared with an irrelevant control VHH. We then used the VHH-peptide platform to evaluate a panel of candidate neoantigens in vivo in a mouse model of pancreatic cancer. None of the candidate neoantigens tested led to protection from tumour challenge; however, we were able to show vaccine-induced CD8 T cell responses to a melanoma self-antigen that was augmented by combination therapy with the synthetic cytokine mimetic Neo2/15.

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