scholarly journals Rapid CLIP dissociation from MHC II promotes an unusual antigen presentation pathway in autoimmunity

2018 ◽  
Vol 215 (10) ◽  
pp. 2617-2635 ◽  
Author(s):  
Yoshinaga Ito ◽  
Orr Ashenberg ◽  
Jason Pyrdol ◽  
Adrienne M. Luoma ◽  
Orit Rozenblatt-Rosen ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Mhc Class Ii ◽  
Antigen Processing ◽  
Class Ii ◽  
Single Amino Acid ◽  
Invariant Chain ◽  
Presentation Pathway ◽  
Single Amino Acid Change

A number of autoimmunity-associated MHC class II proteins interact only weakly with the invariant chain–derived class II–associated invariant chain peptide (CLIP). CLIP dissociates rapidly from I-Ag7 even in the absence of DM, and this property is related to the type 1 diabetes–associated β57 polymorphism. We generated knock-in non-obese diabetic (NOD) mice with a single amino acid change in the CLIP segment of the invariant chain in order to moderately slow CLIP dissociation from I-Ag7. These knock-in mice had a significantly reduced incidence of spontaneous type 1 diabetes and diminished islet infiltration by CD4 T cells, in particular T cells specific for fusion peptides generated by covalent linkage of proteolytic fragments within β cell secretory granules. Rapid CLIP dissociation enhanced the presentation of such extracellular peptides, thus bypassing the conventional MHC class II antigen-processing pathway. Autoimmunity-associated MHC class II polymorphisms therefore not only modify binding of self-peptides, but also alter the biochemistry of peptide acquisition.

scholarly journals Position β57 of I-Ag7 controls early anti-insulin responses in NOD mice, linking an MHC susceptibility allele to type 1 diabetes onset

2019 ◽  
Vol 4 (38) ◽  
pp. eaaw6329 ◽  
Author(s):  
Louis Gioia ◽  
Marie Holt ◽  
Anne Costanzo ◽  
Siddhartha Sharma ◽  
Brian Abe ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Disease Onset ◽  
Insulin Response ◽  
Nod Mice ◽  
Class Ii ◽  
Single Amino Acid ◽  
Specific Gene ◽  
Single Amino Acid Change

The class II region of the major histocompatibility complex (MHC) locus is the main contributor to the genetic susceptibility to type 1 diabetes (T1D). The loss of an aspartic acid at position 57 of diabetogenic HLA-DQβ chains supports this association; this single amino acid change influences how TCRs recognize peptides in the context of HLA-DQ8 and I-Ag7 using a mechanism termed the P9 switch. Here, we built register-specific insulin peptide MHC tetramers to examine CD4+ T cell responses to Ins12–20 and Ins13–21 peptides during the early prediabetic phase of disease in nonobese diabetic (NOD) mice. A single-cell analysis of anti-insulin CD4+ T cells performed in 6- and 12-week-old NOD mice revealed tissue-specific gene expression signatures. TCR signaling and clonal expansion were found only in the islets of Langerhans and produced either classical TH1 differentiation or an unusual Treg phenotype, independent of TCR usage. The early phase of the anti-insulin response was dominated by T cells specific for Ins12–20, the register that supports a P9 switch mode of recognition. The presence of the P9 switch was demonstrated by TCR sequencing, reexpression, mutagenesis, and functional testing of TCRαβ pairs in vitro. Genetic correction of the I-Aβ57 mutation in NOD mice resulted in the disappearance of D/E residues in the CDR3β of anti-Ins12–20 T cells. These results provide a mechanistic molecular explanation that links the characteristic MHC class II polymorphism of T1D with the recognition of islet autoantigens and disease onset.

Recognition of Ii-Key/MHC Class II Epitope Hybrids Derived from Proinsulin and GAD Peptides by T Cells in Type 1 Diabetes

2011 ◽  
Vol 43 (07) ◽  
pp. 483-488 ◽  
Author(s):  
M. Vadacca ◽  
M. G. Valorani ◽  
E. von Hofe ◽  
N. L. Kallinteris ◽  
R. Buzzetti ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Mhc Class Ii ◽  
Class Ii

scholarly journals HLA Class II Antigen Processing and Presentation Pathway Components Demonstrated by Transcriptome and Protein Analyses of Islet β-Cells From Donors With Type 1 Diabetes

Diabetes ◽  
2019 ◽  
Vol 68 (5) ◽  
pp. 988-1001 ◽  
Author(s):  
Mark A. Russell ◽  
Sambra D. Redick ◽  
David M. Blodgett ◽  
Sarah J. Richardson ◽  
Pia Leete ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Antigen Processing ◽  
Class Ii ◽  
Hla Class Ii ◽  
Β Cells ◽  
Presentation Pathway ◽  
Class Ii Antigen ◽  
Antigen Processing And Presentation

GAD65- and proinsulin-specific CD4+ T-cells detected by MHC class II tetramers in peripheral blood of type 1 diabetes patients and at-risk subjects

2005 ◽  
Vol 25 (3) ◽  
pp. 235-243 ◽  
Author(s):  
Viveka Öling ◽  
Jane Marttila ◽  
Jorma Ilonen ◽  
William W. Kwok ◽  
Gerald Nepom ◽  
...  
Keyword(s):  
At Risk ◽  
T Cells ◽  
Type 1 Diabetes ◽  
Mhc Class Ii ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Diabetes Patients

scholarly journals Specificity of Effector T Lymphocytes in Autologous Graft-Versus-Host Disease: Role of the Major Histocompatibility Complex Class II Invariant Chain Peptide

Blood ◽  
1997 ◽  
Vol 89 (6) ◽  
pp. 2203-2209 ◽  
Author(s):  
Allan D. Hess ◽  
Emilie C. Bright ◽  
Christopher Thoburn ◽  
Georgia B. Vogelsang ◽  
Richard J. Jones ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Lymphocytes ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Effector T Cells ◽  
Invariant Chain ◽  
Target Cells ◽  
Graft Versus Host ◽  
Histocompatibility Complex

Abstract Administration of the immunosuppressive drug cyclosporine after autologous bone marrow transplantation induces a systemic autoimmune syndrome resembling graft-versus-host disease (GVHD). This syndrome termed autologous GVHD has significant antitumor activity. Associated with autologous GVHD is the development of T lymphocytes that recognize major histocompatibility complex (MHC) class II determinants, including self. The present studies attempted to characterize and define the molecular specificity of the effector T lymphocytes in autologous GVHD induced in patients with metastatic breast cancer. The results suggest that the effector cells associated with human autologous GVHD are CD8+ T lymphocytes expressing the α/β T-cell receptor. Additional studies show that the effector T cells recognize MHC class II antigens in association with a peptide from the invariant chain (CLIP). Pretreatment of autologous lymphoblast target cells with anti-CLIP antibody completely blocked lysis mediated by autologous GVHD effector T cells. On the other hand, force loading this peptide markedly enhanced the susceptibility of the target cells to recognition by the autoreactive T cells. The recognition of the MHC class II CLIP complex may account for the novel specificity of the effector T cells associated with human autologous GVHD. Moreover, identification of the target peptide may allow for the development of novel immunotherapeutic strategies to enhance the antitumor efficacy of autologous GVHD.

scholarly journals Invariant chain and DM edit self-peptide presentation by major histocompatibility complex (MHC) class II molecules.

1996 ◽  
Vol 184 (5) ◽  
pp. 1747-1753 ◽  
Author(s):  
J F Katz ◽  
C Stebbins ◽  
E Appella ◽  
A J Sant
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Binding Pocket ◽  
Surface Expression ◽  
Class Ii ◽  
Invariant Chain ◽  
Generalized Function ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

We have studied the consequences of invariant chain (Ii) and DM expression on major histocompatibility complex (MHC) class II function. Ii has a number of discrete functions in the biology of class II, including competitive blocking of peptide binding in the endoplasmic reticulum and enhancing localization in the endocytic compartments. DM is thought to act primarily in endosomes to promote dissociation of the Ii-derived (CLIP) peptide from the class II antigen-binding pocket and subsequent peptide loading. In this study, we have evaluated the functional role of Ii and DM by examining their impact on surface expression of epitopes recognized by a large panel of alloreactive T cells. We find most epitopes studied are influenced by both Ii and DM. Most strikingly, we find that surface expression of a significant fraction of peptide-class II complexes is extinguished, rather than enhanced, by DM expression within the APC. The epitopes antagonized by DM do not appear to be specific for CLIP. Finally, we found that DM was also able to extinguish recognition of a defined peptide derived from the internally synthesized H-2Ld protein. Thus, rather than primarily serving in the removal of CLIP, DM may have a more generalized function of editing the array of peptides that are presented by class II. This editing can be either positive or negative, suggesting that DM plays a specifying role in the display of peptides presented to CD4 T cells.

Concomitant Induction of CMVpp65-Specific CD4+ and CD8+ T Cells Using Dendritic Cells Transfected with mRNA Encoding an Invariant Chain-pp65 Fusion Protein.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3243-3243
Author(s):  
Ngocdiep Le ◽  
Jens Dannull ◽  
Nelson Chao ◽  
Johannes Vieweg
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Fusion Protein ◽  
Mhc Class Ii ◽  
Cellular Immunity ◽  
Invariant Chain ◽  
Cell Transplant ◽  
Presentation Pathway ◽  
Cmv Disease ◽  
Ctl Responses

Abstract Human cytomegalovirus (CMV) disease is increasingly recognized as a major cause of morbidity and mortality in post-stem cell transplant (SCT) recipients due to a lack of cellular immunity. Thus, novel therapies that offer the restoration of cellular immunity in SCT patients are highly desirable for clinical use. Cytotoxic T lymphocyte (CTL) responses against CMV represent a major effector arm of the immune system to control viremia. However, it is well established that the efficient induction and persistence of CTL responses in vivo requires the concomitant induction of antigen-specific CD4+ T helper cells. In this study, we sought to determine whether human dendritic cells (DC) transfected with mRNA encoding an invariant chain-CMVpp65 fusion protein (Ii-pp65) were capable of inducing concomitant CMV-specific CTL and CD4+ responses, thereby constituting a useful strategy for immunotherapy of CMV disease. We show that transfection of DC with Ii-pp65 mRNA leads to enhanced stimulation of CMV-specific CTL in vitro (Figure 1). Furthermore, DC expressing Ii-pp65 are potent inducers of primary CMV-specific CD4+ T cell responses as evidenced by ELISPOT analyses of primed CD4+CD45RA+ T cells (Figure 2). Lastly, efficient routing of Ii-pp65 into the MHC class II presentation pathway is demonstrated by confocal microscopy (data not shown). Based on these preclinical findings, we propose a clinical trial to administer DC, transfected with mRNA encoding a chimeric Ii-pp65, to post-SCT patients. Our primary goal will be to prevent CMV infection and reactivation by inducing strong immune reactivities against CMV. Figure Figure

Immune-related gene expression deficit of leukemia stem cells (LSC) in AML.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7011-7011
Author(s):  
Kamal Chamoun ◽  
Christopher Brent Benton ◽  
Ahmed AlRawi ◽  
Rodrigo Jacamo ◽  
Patrick Williams ◽  
...  
Keyword(s):  
Gene Expression ◽  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Antigen Processing ◽  
Differentially Expressed Gene ◽  
Enrichment Analysis ◽  
Class Ii ◽  
Differentially Expressed ◽  
Pathway Gene ◽  
Presentation Pathway

7011 Background: AML LSC are believed to be responsible for residual and resistant leukemic disease leading to relapse. Understanding differences between bulk AML and the LSC subpopulation may allow the identification of novel LSC targets, especially for the most adverse risk AML where few patients are cured. Targeting LSC may be needed to eradicate AML, and immune-based therapies provide an approach for eliminating LSC. The transcriptional landscape of immune-related genes in LSC is not well understood. Methods: Samples were collected at diagnosis from 12 patients with high-risk AML prior to therapy. Bulk (CD45-dim blasts) and LSC (Lin-CD34+CD38-CD123+) AML marrow cells were FACS-sorted and analyzed using whole genome RNA-sequencing. Transcriptomes were analyzed using AltAnalyze software to identify differentially expressed genes in bulk AML cells and in AML LSC populations. These genes were further assessed by gene enrichment analysis using data from Gene Ontology (GO) and the Cancer Genome Atlas Project (CGAP). Results: Sixty-eight genes were identified with greater than 3-fold differential expression between bulk AML and LSC. GO enrichment analysis demonstrated more than 10-fold enrichment of genes involved in the molecular functions, biologic processes, and cell components related to the antigen presentation pathway, with the comparative down-regulation occurring in LSC. Among the top differentially expressed gene clusters, both the MHC class II and interferon-gamma signaling/response pathway gene expression was blunted in LSC. Additional expression analysis revealed that 42% of a CGAP-curated list of 201 antigen-processing and -presentation genes had significantly decreased expression in the LSC subpopulation compared to bulk AML. Conclusions: LSC from primary AML patient samples are characterized by reduction in expression of MHC class II receptor and antigen presentation genes compared to bulk AML. These results suggest that impairment in the presentation and/or processing of tumor associated antigens by MHC class II on LSC, along with tonic sponging of immune response cells and diversion away from LSC by bulk AML, may contribute to LSC evasion of immune surveillance and response.

scholarly journals T cell recognition of major histocompatibility complex class II complexes with invariant chain processing intermediates.

1995 ◽  
Vol 182 (5) ◽  
pp. 1403-1413 ◽  
Author(s):  
S Morkowski ◽  
A W Goldrath ◽  
S Eastman ◽  
L Ramachandra ◽  
D C Freed ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Invariant Chain ◽  
Cell Recognition ◽  
T Cell Recognition ◽  
Histocompatibility Complex ◽  
Mutant Cells

Peptides from the lumenal portion of invariant chain (Ii) spanning residues 80-106 (class II-associated Ii peptide [CLIP]) are found in association with several mouse and human major histocompatibility complex (MHC) class II allelic variants in wild-type and presentation-deficient mutant cells. The ready detection of these complexes suggests that such an intermediate is essential to the MHC class II processing pathway. In this study, we demonstrate that T cells recognize CLIP/MHC class II complexes on the surface of normal and mutant cells in a manner indistinguishable from that of nominal antigenic peptides. Surprisingly, T cell hybrids specific for human CLIP bound to murine MHC class II molecule I-Ab and a new monoclonal antibody 30-2 with the same specificity, recognize two independent epitopes expressed on this peptide/class II complex. T cell recognition is dependent on a Gln residue (position 100) in CLIP, whereas the 30-2 antibody recognizes a Lys residue-at position 90. These two residues flank the 91-99 sequence that is conserved among human, mouse, and rat Ii, potentially representing an MHC class II-binding site. Our results suggest that the COOH-terminal portion of CLIP that includes TCR contact residue Gln 100 binds in the groove of I-Ab molecule. Moreover, both T cells and the antibody recognize I-Ab complexed with larger Ii processing intermediates such as the approximately 12-kD small leupeptin-induced protein (SLIP) fragments. Thus, SLIP fragments contain a CLIP region bound to MHC class II molecule in a conformation identical to that of a free CLIP peptide. Finally, our data suggest that SLIP/MHC class II complexes are precursors of CLIP/MHC class II complexes.

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