scholarly journals P04.03 Immune modulatory vaccine directed against IDO1-expressing immune cells elicits T cell-mediated anti-tumor immunity and enhances anti-PD1 responses

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A37.2-A38
Author(s):  
S Dey ◽  
E Sutanto-Ward ◽  
KL Kopp ◽  
JB DuHadaway ◽  
A Mondal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Tumor Response ◽  
Ex Vivo ◽  
Class Ii ◽  
Class I ◽  
Peptide Vaccines ◽  
Ido1 Expression ◽  
Part Time

BackgroundIndoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme that contributes to immunoregulation at many levels, including suppressing effector T cells and inducing/activating regulatory T cells. Thus far, several therapeutic approaches to target IDO1 enzymatic activity have shown promise in preclinical models, however, results from the first major clinical trial were disappointing. The present study seeks to provide preclinical PoC data for the conceptually unique idea of developing an IDO1-targeted vaccine based on our earlier findings that humans exhibit intrinsic T cell reactivity against IDO1 epitopes1 suggesting the existence of a T cell-mediated, counter-regulatory mechanism directed against cells that express IDO1.Materials and MethodsIDO1-derived peptide vaccines were identified by measurement of vaccine-induced ex vivo response (IFNγ ELISpot) and demonstration of anti-tumor responses in CT26 tumor-bearing mice. To understand the vaccine’s mode of action, resected tumors were analyzed by immunofluorescence microscopy and flow cytometry.ResultsThe CT26 colon carcinoma model was selected for these studies based on evidence of high levels of IDO1 expression and responsiveness to IDO1 inhibition reported for these tumors. In silico-predicted H2d MHC class I and II-restricted IDO1 peptide sequences were tested and vaccine candidates were chosen after confirming ex vivo response and anti-tumor response in CT26. Therapeutic treatment of established CT26 tumors with MHC class I- and II-directed, IDO1-derived peptide vaccines elicited anti-tumor responses when administered alone, and the effect was further pronounced when combined, suggesting distinct mechanisms of action. In addition, a combination of IDO1 vaccine with anti-PD-1 antibody produced a combinatorial anti-tumor response beyond what was achieved with either agent alone. Consistent with this observation, adoptive transfer of isolated CD8+ T cells from class I and CD4+ T cells from class II peptide-vaccinated responder mice delayed tumor growth in treatment naïve mice. The class II-directed response was completely IDO1-dependent while the class I-directed response included an IDO1-independent component indicative of antigen spread. Examination into the tumors in vaccinated mice indicated that IDO1 vaccine treatment exerts its effect by selective reduction of IDO1 expression in the tumor microenvironment and concomitant expansion of activated CD4+ and CD8+ T cells.ConclusionsAs noted in humans, our data demonstrate that IDO1 is immunogenic in mice confirming that this endogenous protein is excluded from normal tolerance mechanisms. The observed immunotherapeutic efficacy of IDO1 peptide vaccines on their own and in combination with anti-PD-1 antibody support the rationale for ongoing clinical development of IDO1 peptide vaccine-based therapy. Future studies include further differentiation of the vaccine platform against other IDO1-targeting approaches, as well as decoding the underlying mechanism of cooperativity between anti-PD-1 antibody and IDO1 peptide vaccines.ReferenceSørensen RB, Hadrup SR, Svane IM, Hjortsø MC, Thor Straten P, Andersen MH. Indoleamine 2,3-dioxygenase specific, cytotoxic T cells as immune regulators. Blood 2011; 117(7): 2200–10Disclosure InformationS. Dey: None. E. Sutanto-Ward: None. K.L. Kopp: A. Employment (full or part-time); Significant; IO Biotech. J.B. DuHadaway: None. A. Mondal: None. I. Lecoq: A. Employment (full or part-time); Significant; IO Biotech. M. Zocca: A. Employment (full or part-time); Significant; IO Biotech. M.H. Andersen: A. Employment (full or part-time); Significant; IO Biotech. A.W. Pedersen: A. Employment (full or part-time); Significant; IO Biotech. A.J. Muller: F. Consultant/Advisory Board; Modest; IO Biotech.

scholarly journals Peptide vaccination directed against IDO1-expressing immune cells elicits CD8+ and CD4+ T-cell-mediated antitumor immunity and enhanced anti-PD1 responses

2020 ◽  
Vol 8 (2) ◽  
pp. e000605
Author(s):  
Souvik Dey ◽  
Erika Sutanto-Ward ◽  
Katharina L Kopp ◽  
James DuHadaway ◽  
Arpita Mondal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Mhc Class I ◽  
Adoptive Transfer ◽  
Immune Cells ◽  
Class Ii ◽  
T Cell Response ◽  
Class I ◽  
Antitumor Effects

BackgroundThe tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which subverts T-cell immunity at multiple levels, is itself subject to inherent T-cell reactivity. This intriguing deviation from central tolerance has been interpreted as counterbalancing IDO1-mediated immunosuppression. Based on this hypothesis, clinical studies employing an IDO1 peptide-based vaccine approach for cancer treatment have been initiated, but there remains a pressing need to further investigate the immunological ramifications of stimulating the anti-IDO1 T-cell response in this manner.MethodsCT26 colon carcinoma tumors were evaluated for expression of IDO1 protein by western blot analysis, immunofluorescence microscopy and flow cytometry. Mouse IDO1-derived peptides, predicted to bind either major histocompatibility complex (MHC) class I or II of the H2d BALB/c strain, were emulsified in 50% Montanide for prophylactic or therapeutic vaccine treatment of CT26 tumor-bearing mice initiated either 7 days prior to or following tumor cell injection, respectively. In some therapeutic treatment experiments, administration of programmed cell death protein 1-binding antibody (anti-PD1 antibody) or epacadostat was concurrently initiated. Tumor size was determined by caliper measurements and comparative tumor growth suppression was assessed by longitudinal analyses of tumor growth data. For adoptive transfer, T cells from complete responder animals were isolated using paramagnetic beads and fluorescence-activated cell sorting.ResultsThis study identifies mouse MHC class I-directed and II-directed, IDO1-derived peptides capable of eliciting antitumor responses, despite finding IDO1 expressed exclusively in tumor-infiltrating immune cells. Treatment of established tumors with anti-PD1 antibody and class I-directed but not class II-directed IDO1 peptide vaccines produced an enhanced antitumor response. Likewise, class I-directed and II-directed IDO1 peptides elicited an enhanced combinatorial response, suggesting distinct mechanisms of action. Consistent with this interpretation, adoptive transfer of isolated CD8+ T cells from class I and CD4+ T cells from class II peptide-vaccinated responder mice delayed tumor growth. The class II-directed response was completely IDO1-dependent while the class I-directed response included an IDO1-independent component consistent with antigen spread.ConclusionsThe in vivo antitumor effects demonstrated with IDO1-based vaccines via targeting of the tumor microenvironment highlight the utility of mouse models for further exploration and refinement of this novel vaccine-based approach to IDO1-directed cancer therapy and its potential to improve patient response rates to anti-PD1 therapy.

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 I and Class II Epitopes of WT1 Using a Peptide Library Screen.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2764-2764 ◽  
Author(s):  
Katayoun Rezvani ◽  
Stephan Mielke ◽  
Yasemin Kilical ◽  
Matthias Grube ◽  
Hiroshi Fujiwara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Class Ii ◽  
Peptide Library ◽  
Class I ◽  
Cell Responses

Abstract Although several HLA-A*0201-restricted immunodominant peptides from the leukemia-restricted protein WT-1 are characterized, T cell responses to peptide sequences binding to other common class I and II epitopes of WT-1 remain almost completely unexplored. A more comprehensive definition of the WT-1 antigen would extend peptide antigen vaccines to individuals lacking HLA-A*0201 and *2402 and improve vaccine potency by recruiting both CD4+ and CD8+ T cell responses. Here we used a WT1 peptide library to identify WT-1 peptide sequences inducing CD4+ and CD8+ T cell responses in normal individuals and patients with AML and other myeloid leukemias. Six cases were studied. The library consisted of 110 15mer peptides overlapping by 11aa covering the entire WT-1 protein in 21 pools. Monocytes were isolated by plastic adherence and pulsed with peptide pools for 3 hours. Autologous CD8+ and CD4+ T cells were then added. Pools of peptides were prepared in such a way that each peptide was represented in two different peptide pools, allowing the identification of the respective peptide by responses in the two corresponding pools. Cells were harvested for RNA extraction and reverse transcription. Real time PCR (RQ-PCR) was used to identify peptide-specific induction of IFN-γ and IL-2 in CD8+ and CD4+ T cells. The SYFPEITHI binding motif software was then used to predict the probable HLA restriction for the candidate epitopes. To confirm candidate peptide immunogenecity and HLA restriction, selected peptides were synthesized and tested individually. In addition to the known HLA-A*0201 peptides WT37, WT126, WT187 and WT235 we identified 20 new MHC class I and II epitopes of WT1. Four were restricted by more than one HLA allele, demonstrating the promiscuity of epitope binding. One epitope (VPGVAPTLV) was restricted to HLA-A*0201 and HLA-B*5101. One epitope (SGQFTGTAGACRYGP) was restricted by a class I HLA allele, namely HLA-*6801 and a class II HLA allele, DR*1501. Two epitopes (YGPFGPPPPSQASGQ and QKKFARSDELVRHHN) were restricted by multiple MHC class II alleles. The proliferative response of CD4+ and CD8+ T cells to candidate peptides was confirmed using CFSE labeling. We now plan to characterize the antileukemic effects of CD4+ and CD8+ T cells induced by these peptides with a view to designing broad-spectrum vaccines inducing leukemia-reactive T cells across a wide range of HLA types.

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.

Sequence Dependent Efficiency of Cross-Presentation in MHC Class I Requires Rational Design of Long Synthetic Peptides for Vaccination or Ex Vivo Activation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3904-3904
Author(s):  
Maarten L. Zandvliet ◽  
J.H. Frederik Falkenburg ◽  
Michel G.D. Kester ◽  
Arnoud H. de Ru ◽  
Peter A. van Veelen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Synthetic Peptides ◽  
Ex Vivo ◽  
Class I ◽  
Cross Presentation ◽  
Cell Responses

Abstract For the induction or boosting of antigen-specific CD8+ T cell responses, long synthetic peptides have been used in vaccination studies. Superior in vivo CD8+ T cell responses have been reported following vaccination with long peptides compared with minimal peptides, which was attributed to selective uptake and cross-presentation by professional antigen-presenting cells. Furthermore, to generate antigen-specific T cell lines for adoptive immunotherapy or to measure antigen-specific T cell responses, protein-spanning pools of overlapping long synthetic peptides can be used to simultaneously activate CD8+ and CD4+ T cells in peripheral blood mononuclear cells (PBMC) ex vivo. Although exogenous antigen is predominantly presented in MHC class II, it has been suggested that cross-presentation of long peptides in MHC class I can occur. However, the mechanism of cross-presentation of exogenous long peptides in MHC class I is not clear. Various models for cross-presentation have been described following uptake of soluble antigen in endosomes, among which antigen transport over the endosomal membrane followed by the classical proteasome- and TAP-dependent route, and entrance of MHC class I in the recycling endocytic MHC class II pathway where peptidase-trimmed exogenous antigens can exchange with peptides in the MHC class I molecules, resulting in TAP- and proteasome-independent cross-presentation. To improve the design of peptides for the in vivo or ex vivo activation of CD8+ T cells we investigated the mechanism and efficiency of cross-presentation of long peptides. We observed that antigen-presenting cells in peripheral blood, in particular monocytes, loaded with 15-mer peptides, 31-mer peptides or full length protein containing the NLV epitope were able to very efficiently induce IFNg production by cytomegalovirus (CMV) pp65 NLV-specific T cells. Specific T cells were most efficiently activated by N-terminally extended variants of the minimal epitope, while the use of C-terminally extended variants resulted in a 10-fold reduction of activation efficiency. Purification of these antigens by high performance liquid chromatography (HPLC) followed by mass spectrometry demonstrated that activation was not caused by contamination with the minimal epitope sequence. Also CD8+ T cells specific for other CMV and minor histocompatibility antigen (mHag) epitopes were activated by monocytes loaded with 15-mer or 20-mer peptides. Again N-terminally extended variants of minimal epitopes very efficiently induced activation, while the use of C-terminally variants or full length protein resulted in highly variable efficiency of activation, ranging from 10-fold reduction to complete absence of activation. Interestingly, TAP-deficient T2 cells loaded with CMV pp65 NLV antigens also efficiently activated NLV-specific T cells, indicating that the route of presentation was TAP-independent. Addition of lactacystin during loading of monocytes with CMV pp65 NLV 15-mer did not affect activation of specific T cells, suggesting that cross-presentation was proteasome-independent. Addition of primaquine reduced activation of specific T cells by the NLV 15-mer peptide, but not by the minimal NLV 9-mer peptide, suggesting that cross-presentation was dependent on endosomal recycling. To compare cross-presentation with presentation of endogenously synthesized antigen, TAP-competent T1 and TAP-deficient T2 cells were retrovirally transduced with the CMV pp65 gene. CMV pp65-specific T cells were activated by CMV pp65 transduced T1 but not T2 cells, indicating that endogenously synthesized CMV pp65 required processing and presentation by the classical proteasome- and TAP-dependent route. These data suggest that long synthetic peptides can be processed by peptidases in endocytic compartments and presented by recycling MHC class I molecules. Not all immunogenic epitopes that have been selected in vivo for efficient processing and presentation by the classical pathway may be presented efficiently by cross-presentation. As the efficiency of cross-presentation of long synthetic peptides may depend on the sequence of the C-terminal extension, a rational design of peptides is crucial for efficient activation of CD8+ T cells in approaches of vaccination, adoptive transfer and immune monitoring.

scholarly journals P09.07 An immune modulatory vaccine targeting CCL22 promotes anti-tumor immunity

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A55.1-A55
Author(s):  
I Lecoq ◽  
KL Kopp ◽  
R Christensen ◽  
E Martinenaite ◽  
AW Pedersen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Modulation ◽  
Ex Vivo ◽  
Mouse Tumor ◽  
Peptide Vaccines ◽  
Tumor Models ◽  
Cancer Immunity ◽  
Anti Cancer ◽  
Part Time

BackgroundCCL22 is a macrophage-derived chemokine that exerts immunosuppressive functions by the recruitment of regulatory T cells (Treg) through the CCL22/CCR4 axis. It has been described to play a key role in the suppression of anti-cancer immunity in different cancer types including ovarian, breast, or pancreatic cancer and is thought to promote the suppression of anti-cancer immunity by Treg recruitment. Recently, we described that CCL22-specific T cells generated from cancer patients can kill CCL22-expressing tumor cells and directly influence the level of CCL22 in vitro.1 In this study, we provide PoC data for a CCL22-targeting vaccine by assessing the immunotherapeutic efficacy of this approach in syngeneic mouse tumor models.Materials and MethodsPeptide vaccines that induce expansion of CCL22-specific T cells were identified by measurement of vaccine-induced ex vivo response (IFNγ ELISpot) in BALB/c and C57BL/6 mice. The antitumor efficacy was evaluated in CT26, Pan02 and B16 syngeneic models. To investigate the vaccine’s mode of action, the tumor immune infiltration was analyzed through flow cytometry and qPCR.ResultsVaccination with CCL22-specific peptide vaccines induced expansion of primarily CD8+, CCL22-specific T cell responses (assessed by ex vivo IFNγ ELISpot). Treatment with CCL22 vaccines reduced tumor growth and increased survival in CT26, Pan02 and B16 tumor models. Assessment of gene expression in the tumors indicated that vaccination leads to a reduction of CCL22 expression in the tumor microenvironment (TME), as well as the expression of other immune-suppressive molecules such as IDO. Furthermore, vaccinated mice harbored an increased CD8+ T cell infiltration with a concomitant increase in M1/M2 ratio within the TME.ConclusionsThis study provides evidence that targeting CCL22 expressing cells by vaccination induces immune modulation in the TME, leading to augmentation of anti-tumor responses - thus provides a rationale for a novel immunotherapeutic approach in cancer.Disclosure InformationI. Lecoq: A. Employment (full or part-time); Modest; IO Biotech. K.L. Kopp: A. Employment (full or part-time); Modest; IO Biotech. R. Christensen: A. Employment (full or part-time); Modest; IO Biotech. E. Martinenaite: A. Employment (full or part-time); Modest; IO Biotech. A.W. Pedersen: A. Employment (full or part-time); Modest; IO Biotech. M.H. Andersen: A. Employment (full or part-time); Modest; IO Biotech.

MHC Sınıf I ve MHC Sınıf II Gen Düzenlenmesi

2020 ◽  
Vol 8 (3) ◽  
pp. 144-156
Author(s):  
Şule KARATAŞ ◽  
Fatma SAVRAN OĞUZ
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Gene Regulation ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Class I ◽  
Mhc Molecules ◽  
Class Ii Mhc ◽  
Regulation Mechanisms

Introduction: Peptides obtained by processing intracellular and extracellular antigens are presented to T cells to stimulate the immune response. This presentation is made by peptide receptors called major histocompatibility complex (MHC) molecules. The regulation mechanisms of MHC molecules, which have similar roles in the immune response, especially at the gene level, have significant differences according to their class. Objective: Class I and class II MHC molecules encoded by MHC genes on the short arm of the sixth chromosome are peptide receptors that stimulate T cell response. These peptides, which will enable the recognition of the antigen from which they originate, are loaded into MHC molecules and presented to T cells. Although the principles of loading and delivering peptides are similar for both molecules, the peptide sources and peptide loading mechanisms are different. In addition, class I molecules are expressed in all nucleated cells while class II molecules are expressed only in Antigen Presentation Cells (APC). These differences; It shows that MHC class I is not expressed by exactly the same transcriptional mechanisms as MHC class II. In our article, we aimed to compare the gene expressions of both classes and reveal their similarities and differences. Discussion and Conclusion: A better understanding of the transcriptional mechanisms of MHC molecules will reveal the role of these molecules in diseases more clearly. In our review, we discussed MHC gene regulation mechanisms with presence of existing informations, which is specific to the MHC class, for contribute to future research. Keywords: MHC class I, MHC class II, MHC gene regulation, promoter, SXY module, transcription

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

T-cell epitopes within the complementarity-determining and framework regions of the tumor-derived immunoglobulin heavy chain in multiple myeloma

Blood ◽  
2003 ◽  
Vol 101 (12) ◽  
pp. 4930-4936 ◽  
Author(s):  
Lotta Hansson ◽  
Hodjattallah Rabbani ◽  
Jan Fagerberg ◽  
Anders Österborg ◽  
Håkan Mellstedt
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Heavy Chain ◽  
T Cell Response ◽  
Class I ◽  
Type I ◽  
T Cell Epitopes ◽  
Hla Binding

Abstract The idiotypic structure of the monoclonal immunoglobulin (Ig) in multiple myeloma (MM) might be regarded as a tumor-specific antigen. The present study was designed to identify T-cell epitopes of the variable region of the Ig heavy chain (VH) in MM (n = 5) using bioinformatics and analyze the presence of naturally occurring T cells against idiotype-derived peptides. A large number of human-leukocyte-antigen (HLA)–binding (class I and II) peptides were identified. The frequency of predicted epitopes depended on the database used: 245 in bioinformatics and molecular analysis section (BIMAS) and 601 in SYFPEITHI. Most of the peptides displayed a binding half-life or score in the low or intermediate affinity range. The majority of the predicted peptides were complementarity-determining region (CDR)–rather than framework region (FR)–derived (52%-60% vs 40%-48%, respectively). Most of the predicted peptides were confined to the CDR2-FR3-CDR3 “geographic” region of the Ig-VH region (70%), and significantly fewer peptides were found within the flanking (FR1-CDR1-FR2 and FR4) regions (P < .01). There were 8– to 10–amino acid (aa) long peptides corresponding to the CDRs and fitting to the actual HLA-A/B haplotypes that spontaneously recognized, albeit with a low magnitude, type I T cells (interferon γ), indicating an ongoing major histocompatibility complex (MHC) class I–restricted T-cell response. Most of those peptides had a low binding half-life (BIMAS) and a low/intermediate score (SYFPEITHI). Furthermore, 15- to 20-aa long CDR1-3–derived peptides also spontaneously recognized type I T cells, indicating the presence of MHC class II–restricted T cells as well. This study demonstrates that a large number of HLA-binding idiotypic peptides can be identified in patients with MM. Such peptides may spontaneously induce a type I MHC class I– as well as class II–restricted memory T-cell response.

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