scholarly journals Identification of MHC class II restricted T-cell-mediated reactivity against MHC class I binding Mycobacterium tuberculosis peptides

Immunology ◽  
2011 ◽  
Vol 132 (4) ◽  
pp. 482-491 ◽  
Author(s):  
Mingjun Wang ◽  
Sheila T. Tang ◽  
Anette Stryhn ◽  
Sune Justesen ◽  
Mette V. Larsen ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Class I

Mouse Schwann cells activate MHC class I and II restricted T-cell responses, but require external peptide processing for MHC class II presentation

2010 ◽  
Vol 37 (2) ◽  
pp. 483-490 ◽  
Author(s):  
Gerd Meyer zu Hörste ◽  
Holger Heidenreich ◽  
Anne K. Mausberg ◽  
Helmar C. Lehmann ◽  
Anneloor L.M.A. ten Asbroek ◽  
...  
Keyword(s):  
T Cell ◽  
Schwann Cells ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
T Cell Responses ◽  
Class Ii ◽  
Class I ◽  
Peptide Processing ◽  
Cell Responses

Predicting promiscuous antigenic T cell epitopes of Mycobacterium tuberculosis mymA operon proteins binding to MHC Class I and Class II molecules

2016 ◽  
Vol 44 ◽  
pp. 182-189 ◽  
Author(s):  
Iti Saraav ◽  
Kirti Pandey ◽  
Monika Sharma ◽  
Swati Singh ◽  
Prasun Dutta ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Mhc Class I ◽  
Class Ii ◽  
Class I ◽  
T Cell Epitopes

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.

Identification of Novel MHC Class II-Restricted Male-Specific mHAg Encoded bySMCY(JARID1D)..

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1344-1344
Author(s):  
Nobuharu Fujii ◽  
Kellie V Rosinski ◽  
Paulo V Campregher ◽  
Edus H Warren
Keyword(s):  
T Cell ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Cell Clone ◽  
T Cell Responses ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Class I ◽  
Cell Responses ◽  
T Cell Clone

Abstract Abstract 1344 Poster Board I-366 Male recipients of female hematopoietic cell grafts, when compared with all other donor/recipient gender combinations, have an increased risk for both acute and chronic GVHD, but also have a significantly decreased risk of posttransplant relapse. F→M HCT is also characterized at the cellular level by donor (female) T cell responses against male-specific minor histocompatibility (H-Y) antigens, which can contribute to both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) activity. SMCY is a Y-chromosome gene that has previously been shown to encode at least two distinct MHC class I-restricted H-Y antigens presented by HLA-A*0201 and HLA-B*0702, respectively. Also, association between CD8+ T cell responses specific for the SMCY311-319 FIDSYICQV epitope and GVHD or GVL has been reported. A CD8+ FIDSYICQV-specific T cell clone was also reported to induce histological signs of GVHD reaction in an in vitro skin-explant assay. To date, however, only two MHC class I-restricted, and no MHC class II-restricted, H-Y antigens encoded by SMCY have been characterized. Given the large size of the SMCY and the homologous SMCX proteins and the fact that they are only 85% identical at the amino acid sequence level, we hypothesized that SMCY encodes other MHC class I- and class II-restricted H-Y antigens, and that T cell responses against these epitopes may likewise contribute to GVHD and GVL activity after F→M HCT. Arrays of pentadecapeptides with eleven-residue overlap were designed to tile regions of the SMCY protein that are non-identical to the corresponding regions of its X chromosome-encoded homologue SMCX, and then used to generate SMCY-specific T cell lines recognizing novel SMCY-encoded MHC class I- and class II-restricted H-Y antigens. Peripheral blood mononuclear cells (PBMC) were obtained on posttransplant day +126 from a 46 year-old male patient with monosomy 7 AML who had received a hematopoietic cell graft from his MHC-identical sister, and were stimulated in vitro with dendritic cells derived from his pretransplant PBMC that had been pulsed with the SMCY pentadecapeptides. After three stimulations, a SMCY peptide-specific CD4+ T cell line as well as a SMCY311-319 (FIDSYICQV)-specific CD8+ T cell line were obtained. After cloning by limiting dilution, we further characterized the SMCY-specific CD4+ T cell clone, 13H3. The 13H3 T cell clone recognizes the SMCY232-246 15-mer peptide, ELKKLQIYGPGPKMM, presented by HLA-DRB1*1501, and has a CD3+, CD4+, CD8−, CD45RA−, CD45RO+ surface phenotype. The cytokine release profile of this clone when assessed with SMCY232-246-loaded donor-derived EBV-LCL, as measured by the Luminex assay, is characterized mainly by Th1 cytokines (IFN-g and IL-2), but the clone also produced low to moderate levels of the Th2 cytokines IL-4, IL-10, and TGF-β. A minigene encoding SMCY232-246 was recognized by the 13H3 clone in a HLA-DRB1*1501-dependent fashion when transfected into COS-7 cells, but a minigene encoding the homologous SMCX-derived ELKKLQIYGAGPKMM peptide was not recognized, demonstrating that the clone is SMCY-specific. The 13H3 clone recognized 3 of 5 HLA-DRB1*1501+ male primary leukemia cells, but did not recognize either of 2 HLA-DRB1*1501− male or either of 2 HLA-DRB1*1501+ female primary leukemia cells. These results suggest that CD4+ T cell responses against the SMCY232-246 epitope could potentially contribute to GVL activity after F→M HCT. A SMCY232-246/HLA-DRB1*1501 tetramer has been constructed which specifically marks the 13H3 T cell clone, and future studies will use this reagent to determine whether CD4+ T cells specific for this epitope can be detected directly ex vivo in posttransplant blood samples from HLA-DRB1*1501+ F→M HCT recipients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Structural modeling and conserved epitopes prediction against SARS-COV-2 structural proteins for vaccine development

2020 ◽  
Author(s):  
Muhammad Tahir ul Qamar ◽  
Farah Shahid ◽  
Usman Ali Ashfaq ◽  
Sidra Aslam ◽  
Israr Fatima ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Class I ◽  
Structural Proteins ◽  
Severe Illness ◽  
T Cell Epitopes ◽  
B Cell Epitopes

Abstract Background: Coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Corona virus 2 (SARS-COV-2) was first diagnosed in December 2019, Wuhan, China. Little is known about this new virus and it has the potential to cause severe illness and pneumonia in some people, therefore the development of an effective vaccine is highly desired.Methods: Immunoinformatics and statistical approaches were used in this study to forecast B- and T- cell epitopes for the SARS-COV-2 structural proteins (Surface glycoprotein, Envelope protein, and Membrane glycoprotein) that may play a key role in eliciting immune response against COVID-19. Different types of B cell epitopes (linear as well as discontinuous) and T cell (MHC class I and MHC class II) were determined. Moreover, their antigenicity and allergenicity were also estimated.Results: The antigenic B-cell epitopes exposed to the outer surface were screened out and 23 linear B cell epitopes were selected. “SPTKLNDLCFTNVY” had the highest antigenicity score among B cell epitopes. The T-cell epitopes bound to multiple alleles, antigenic, non-allergen, non-toxic, and conserved in the protein sequence were shortlisted. In total, 16 epitopes (9 from MHC class I and 7 from MHC class II) were selected. Among the T-cell epitopes, MHC class I (IPFAMQMAYRFN) and MHC class II (VTLACFVLAAVYRIN) were classified as strongly antigenic. Digestion analysis verified the safety and stability of the peptides predicted during this study. Furthermore, docking analyses of predicted peptides showed significant interactions with the HLA-B7 allele.Conclusion: The putative antigen epitopes identified in this study may serve as vaccine candidates and can help to eliminate/control growing health threat of COVID-19.

scholarly journals Homologies between SARS-CoV-2 and allergen proteins may direct T cell-mediated heterologous immune responses

2020 ◽  
Author(s):  
Kathrin Balz ◽  
Meng Chen ◽  
Abhinav Kaushik ◽  
Franz Cemic ◽  
Vanessa Heger ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
De Novo ◽  
Class Ii ◽  
Cross Reactivity ◽  
Phleum Pratense ◽  
Class I ◽  
T Cell Epitopes ◽  
Allergen Sources

Abstract The outbreak of the new Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a public health emergency. Asthma does not represent a risk factor for COVID-19 in several published cohorts. We hypothesized that the SARS-CoV-2 proteome contains T cell epitopes, which are potentially cross-reactive to allergen epitopes. We aimed at identifying homologous peptide sequences by means of two distinct complementary bioinformatics approaches. Pipeline 1 included prediction of MHC Class I and Class II epitopes contained in the SARS-CoV-2 proteome and allergens along with alignment and elaborate ranking approaches. Pipeline 2 involved alignment of SARS-CoV-2 overlapping peptides with known allergen-derived T cell epitopes. Our results indicate a large number of MHC Class I epitope pairs including known as well as de novo predicted allergen T cell epitopes with high probability for cross-reactivity. Allergen sources, such as Aspergillus fumigatus, Phleum pratense and Dermatophagoides species are of particular interest due to their association with multiple cross-reactive candidate peptides, independently of the applied bioinformatic approach. In contrast, peptides derived from food allergens, as well as MHC class II epitopes did not achieve high in silico ranking and were therefore not further investigated. Our findings warrant further experimental confirmation along with examination of the functional importance of such cross-reactive responses.

Cell-Autonomous Upregulation of Dendritic Cell Immunocompetence Is Antigen-Dependent.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2230-2230
Author(s):  
William K. Decker ◽  
Dongxia Xing ◽  
Sufang Li ◽  
Richard E. Champlin ◽  
John D. McMannis ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Line ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Fold Increase ◽  
Surface Expression ◽  
Class Ii ◽  
Class I ◽  
Antigenic Determinants ◽  
T Cell Help

Abstract Introduction: Dendritic cells (DCs) are the master regulators of the adaptive immune response. In previous experiments, the double-loading of DCs with matched sets of MHC class I and class II repertoires (i.e. mRNA and cell lysate derived from the same source) appeared to enhance T-cell responses by maximizing the availability of T-cell help. T-cell help, provided by accessory CD4+ lymphocytes, elevates DC immunocompetence in response to antigen-specific interactions between the T-cell receptor and the peptide antigen/MHC class II complex. While T-cell help is specific and aids in the priming of only cognate CD8+ effectors, the mechanism governing this specificity is not understood. Here, we have explored the hypothesis that the specificity of T-cell help may be initiated by the DC itself upon detection of an antigen-dependent signal: the loading of the DC with matched sets of class I and class II determinants. Methods: To examine this hypothesis, we doubly-loaded DCs with either matched sets of antigenic determinants derived from acute myelogenous leukemia (AML) mRNA and lysate preparations, or, mismatched sets of antigenic preparations derived from AML products, the human TF-1a erythroblastic cell line, or the murine FBMD-1 stromal cell line. Following loading and maturation, we analyzed DCs for markers of immunocompetence such as IL-12 secretion and CD83 surface expression. Using specific siRNA oligonucleotides, we also examined a possible role for the intracellular CD63 tetraspanin in this process. DCs were generated by CD14 magnetic selection of apheresis products and six days of culture in GM-CSF and IL-4. Analysis of immature DCs at this time point by flow cytometry typically showed a CD3+ content equivalent to or less than that of the isotype control. DCs were then loaded with either matched or mismatched sets of determinants (as described above) and matured. Results: Matched-loaded DCs exhibited a 4-fold increase in IL-12 secretion over unloaded DCs while mismatch-loaded DCs showed only a 0.7-fold increase (similar to controls) (p = 0.0086). Moreover, matched-loaded DCs demonstrated a 21% increase in CD83 surface expression over unloaded/singly-loaded controls while mismatch-loaded DCs showed only a 6% increase (statistically identical to controls) (p = 0.009). In a single-antigen model system, electroporation of CD63 siRNA could reduce IL-12 secretion from matched-loaded DCs by 60% in comparison to matched-loaded DCs electroporated with non-targeting siRNAs. Secretion of non-Th-1 cytokines (i.e. IL-10) was unaffected. Conclusions: It appears that DC immunocompetence may be upregulated in a cell-autonomous, antigen-dependent fashion. Such upregulation is induced by the loading of DCs with matched sets of MHC class I and class II antigenic determinants and does not occur if DCs are loaded with mismatched determinants. CD63 appears to be involved in this process. CD63 is a member of the tetraspanin family of integral membrane proteins, molecules that facilitate the interaction of membrane and intracellular signaling complexes. In DCs, CD63 is localized exclusively to lysosomal exosomes, sites at which MHC class II, MHC class I, and phagocytosed antigens also co-localize. The data are suggestive of a cross-licensing model by which T-cell help might first be solicited by DCs loaded with matched antigenic determinants. Permission granted by a receptive DC, the helper T-cell might then license DC priming of CD8+ responses. Confirmatory studies are in progress.

scholarly journals Mapping and restriction of a dominant viral CD4+ T cell core epitope by both MHC class I and MHC class II

Virology ◽  
2007 ◽  
Vol 363 (1) ◽  
pp. 113-123 ◽  
Author(s):  
Dirk Homann ◽  
Hanna Lewicki ◽  
David Brooks ◽  
Jens Eberlein ◽  
Valerie Mallet-Designé ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Class I

scholarly journals Mechanisms of mouse spleen dendritic cell function in the generation of influenza-specific, cytolytic T lymphocytes.

1992 ◽  
Vol 176 (2) ◽  
pp. 519-529 ◽  
Author(s):  
R Nonacs ◽  
C Humborg ◽  
J P Tam ◽  
R M Steinman
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Cell Function ◽  
Class Ii ◽  
T Cell Response ◽  
Class I

We have evaluated the capacity of dendritic cells to function as antigen-presenting cells (APCs) for influenza and have examined their mechanism of action. Virus-pulsed dendritic cells were 100 times more efficient than bulk spleen cells in stimulating cytotoxic T lymphocyte (CTL) formation. The induction of CTLs required neither exogenous lymphokines nor APCs in the responding T cell population. Infectious virus entered dendritic cells through intracellular acidic vacuoles and directed the synthesis of several viral proteins. If ultraviolet (UV)-inactivated or bromelain-treated viruses were used, viral protein synthesis could not be detected, and there was poor induction of CTLs. This indicated that dendritic cells were not capable of processing noninfectious virus onto major histocompatibility complex (MHC) class I molecules. However, UV-inactivated and bromelain-treated viruses were presented efficiently to class II-restricted CD4+ T cells. The CD4+ T cells crossreacted with different strains of influenza and markedly amplified CTL formation. Cell lines that lacked MHC class II, and consequently the capacity to stimulate CD4+ T cells, failed to induce CTLs unless helper lymphokines were added. Similarly, dendritic cells pulsed with the MHC class I-restricted nucleoprotein 147-155 peptide were poor stimulators in the absence of exogenous helper factors. We conclude that the function of dendritic cells as APCs for the generation of virus-specific CTLs in vitro depends measurably upon: (a) charging class I molecules with peptides derived from endogenously synthesized viral antigens, and (b) stimulating a strong CD4+ helper T cell response.

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