MHC Class II Associations with Autoantibody and T cell Immune Responses to the Scleroderma Autoantigen Topoisomerase I

ABSTRACT Dendritic cells (DCs) are professional antigen-presenting cells which initiate and regulate T-cell immune responses. Here we show that murine splenic DCs can be ranked on the basis of their ability to phagocytose and harbor the obligately intracellular parasite Leishmania major. CD4+ CD8− DCs are the most permissive host cells for L. major amastigotes, followed by CD4− CD8− DCs; CD4− CD8+ cells are the least permissive. However, the least susceptible CD4− CD8+ DC subset was the best interleukin-12 producer in response to infection. Infection did not induce in any DC subset production of the proinflammatory cytokine gamma interferon and nitric oxide associated with the induction of Th1 responses. The number of parasites phagocytosed by DCs was low, no more than 3 organisms per cell, compared to more than 10 organisms per macrophage. In infected DCs, the parasites are located in a parasitophorous vacuole containing both major histocompatibility complex (MHC) class II and lysosome-associated membrane protein 1 molecules, similar to their location in the infected macrophage. The parasite-driven redistribution of MHC class II to this compartment indicates that infected DCs should be able to present parasite antigen.

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Design of a MUC1-based cancer vaccine

Biochemical Society Transactions ◽

10.1042/bst0330705 ◽

2005 ◽

Vol 33 (4) ◽

pp. 705-708 ◽

Cited By ~ 17

Author(s):

F.-G. Hanisch

Keyword(s):

T Cell ◽

Immune Responses ◽

Mhc Class Ii ◽

Cathepsin L ◽

Class Ii ◽

Cytotoxic T Cell ◽

Sequence Variant ◽

Peptide Epitopes ◽

Repeat Domain ◽

Cytotoxic T Cell Responses

The epithelial type 1 transmembrane mucin MUC1 is long-established as a marker for monitoring recurrence of breast cancer, and beyond its diagnostic marker qualities, it is a promising target for immunotherapeutic strategies to treat cancer by active specific immunization. The mucin is able to break tolerance and to induce humoral immune responses in healthy subjects and in cancer patients, but the response is generally weak. These natural responses to tumour-associated MUC1 glycoforms indicate that antibody reactivities are more directed to glycopeptide than to non-glycosylated peptide epitopes. To overcome the weak immunogenicity of heavily O-glycosylated MUC1, the question of whether O-linked glycans remain intact during processing in the MHC class II pathway was addressed. Attempts were made to define site-specific O-glycosylation and the structural requirements for efficient endosomal proteolysis by cathepsin L in dendritic cells. A fraction of glycopeptides survive the processing machinery, and have the capacity to bind to MHC class II and to activate sub-populations of glycopeptide-specific helper T-cell clones as a prerequisite for strong and long-lasting immune responses to MUC1-positive tumours. Moreover, studies on clusters of sequence-variant repeats, which are interspersed in the repeat domain of MUC1 at high frequency, have revealed that a limited set of concerted amino-acid replacements (Asp-Thr0-Arg1–Pro10 to Glu-Ser0-Arg1–Ala10) contributes considerably to increased peptide flexibility and to under-glycosylation of sequence-variant repeats which in concert modify immunological features of the mucin. Peptides and glycopeptides with the immunodominant DTR (Asp-Thr-Arg) or with the variant ESR (Glu-Ser-Arg) motif, and highly immunogenic peptides of the degenerate repeats that flank the repeat domain are currently evaluated as potential targets in multi-epitopic adjuvant-based vaccine strategies for their capacity to induce cytotoxic T-cell responses.

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SUPPRESSION OF HUMAN ANTI-PORCINE T-CELL IMMUNE RESPONSES BY MAJOR HISTOCOMPATIBILITY COMPLEX CLASS II TRANSACTIVATOR CONSTRUCTS LACKING THE AMINO TERMINAL DOMAIN1

Transplantation Journal ◽

10.1097/00007890-199807150-00016 ◽

1998 ◽

Vol 66 (1) ◽

pp. 103-111 ◽

Cited By ~ 20

Author(s):

Sheng Yun ◽

Kenth Gustafsson ◽

John W. Fabre

Keyword(s):

Major Histocompatibility Complex ◽

T Cell ◽

Immune Responses ◽

Major Histocompatibility Complex Class ◽

Class Ii ◽

Complex Class ◽

Class Ii Transactivator ◽

Amino Terminal ◽

Histocompatibility Complex ◽

T Cell Immune Responses

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Humanized E17 Hemophilic Mice Are a Major Breakthrough in the Design of New Preclinical Models for Developing Factor VIII Products with Reduced Immunogenicity.

Blood ◽

10.1182/blood.v110.11.782.782 ◽

2007 ◽

Vol 110 (11) ◽

pp. 782-782 ◽

Cited By ~ 1

Author(s):

Birgit M. Reipert ◽

Christina Hausl ◽

Maria Sasgary ◽

Maria Schuster ◽

Rafi U. Ahmad ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Factor Viii ◽

Mhc Class Ii ◽

Cd4 T Cells ◽

Plasma Cells ◽

Hemophilia A ◽

Class Ii ◽

Mhc Class Ii Molecules

Abstract MHC class II molecules are crucial for regulating adaptive immune responses against self and foreign protein antigens. They determine the antigenic peptides that are presented to CD4+ T cells and are essential for shaping the CD4+ T-cell repertoire in the thymus. Thus, the structure of MHC class II molecules is a major determinant for protein antigen immunogenicity. Structural differences between murine and human MHC class II complexes fundamentally limit the use of conventional murine hemophilia A models for dissecting immune responses to human factor VIII and developing new factor VIII products with reduced immunogenicity. To overcome this limitation, we humanized the murine E17 model of hemophilia A by introducing the human MHC class II haplotype HLA-DRB1*1501 on the background of a complete knockout of all murine MHC class II genes. Any anti-FVIII antibody response in this new humanized hemophilia A model is driven by CD4+ T cells that recognize FVIII-derived peptides that are presented by human HLA-DRB1*1501. The MHC class II haplotype HLA-DRB1*1501 is particularly relevant for the situation in hemophilia A patients because it is found in about 25% of Caucasians and 32% of Africans and has been shown to be associated with an increased risk that patients with severe hemophilia A have for developing FVIII inhibitors. We validated the relevance of this new model by asking the question whether HLA-DRB1*1501 hemophilic E17 mice develop FVIII inhibitors that are similar to those observed in patients with hemophilia A. Furthermore, we wanted to show that anti-FVIII antibody responses in these mice depend on the expression of the human DRB1*1501 molecule. Mice were treated with 8 intravenous doses of human FVIII and tested for anti-FVIII antibodies, anti-FVIII antibody-producing plasma cells and FVIII-specific T cells. About 90% of all humanized hemophilic E17 mice tested developed anti-FVIII antibodies that were similar to FVIII inhibitors found in patients. These antibodies were not restricted isotypically and contained mainly IgG1, IgG2a and IgG2b antibodies. Detection of antibodies in the circulation correlated with the presence of anti-FVIII antibody-producing plasma cells in the spleen. Development of anti-FVIII antibodies depended on the activation of FVIII-specific T cells and strictly depended on the expression of the HLA-DRB1*1501 molecule. Mice that did not express any MHC class II molecules did not develop anti-FVIII antibodies. We conclude that this new humanized E17 model for hemophilia A is a major advance towards developing suitable animal models needed to design future immunomodulatory strategies for patients with FVIII inhibitors and develop new FVIII products with reduced immunogenicity. Furthermore, it provides a tool for identifying T-cell epitopes of human FVIII restricted by MHC class II molecules that can be used for monitoring FVIII-specific T cells in patients who receive replacement therapy with FVIII products.

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MHC class II invariant chain–adjuvanted viral vectored vaccines enhances T cell responses in humans

Science Translational Medicine ◽

10.1126/scitranslmed.aaz7715 ◽

2020 ◽

Vol 12 (548) ◽

pp. eaaz7715

Author(s):

Ilaria Esposito ◽

Paola Cicconi ◽

Anna Morena D’Alise ◽

Anthony Brown ◽

Marialuisa Esposito ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Mhc Class Ii ◽

T Cell Activation ◽

Critical Role ◽

T Cell Responses ◽

Class Ii ◽

Effector Memory ◽

Invariant Chain ◽

Cell Responses

Strategies to enhance the induction of high magnitude T cell responses through vaccination are urgently needed. Major histocompatibility complex (MHC) class II–associated invariant chain (Ii) plays a critical role in antigen presentation, forming MHC class II peptide complexes for the generation of CD4+ T cell responses. Preclinical studies evaluating the fusion of Ii to antigens encoded in vector delivery systems have shown that this strategy may enhance T cell immune responses to the encoded antigen. We now assess this strategy in humans, using chimpanzee adenovirus 3 and modified vaccinia Ankara vectors encoding human Ii fused to the nonstructural (NS) antigens of hepatitis C virus (HCV) in a heterologous prime/boost regimen. Vaccination was well tolerated and enhanced the peak magnitude, breadth, and proliferative capacity of anti-HCV T cell responses compared to non-Ii vaccines in humans. Very high frequencies of HCV-specific T cells were elicited in humans. Polyfunctional HCV-specific CD8+ and CD4+ responses were induced with up to 30% of CD3+CD8+ cells targeting single HCV epitopes; these were mostly effector memory cells with a high proportion expressing T cell activation and cytolytic markers. No volunteers developed anti-Ii T cell or antibody responses. Using a mouse model and in vitro experiments, we show that Ii fused to NS increases HCV immune responses through enhanced ubiquitination and proteasomal degradation. This strategy could be used to develop more potent HCV vaccines that may contribute to the HCV elimination targets and paves the way for developing class II Ii vaccines against cancer and other infections.

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Long-term surviving cancer patients as a source of therapeutic TCR

Cancer Immunology Immunotherapy ◽

10.1007/s00262-019-02468-9 ◽

2020 ◽

Vol 69 (5) ◽

pp. 859-865 ◽

Cited By ~ 4

Author(s):

Else Marit Inderberg ◽

Sébastien Wälchli

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Mhc Class Ii ◽

Therapeutic Potential ◽

Cancer Control ◽

Class Ii ◽

The Cost

AbstractWe have established a platform for the isolation of tumour-specific TCR from T cells of patients who experienced clinical benefit from cancer vaccination. In this review we will present the rationale behind this strategy and discuss the advantages of working with “natural” wild type TCRs. Indeed, the general trend in the field has been to use various modifications to enhance the affinity of such therapeutic TCRs. This was done to obtain stronger T cell responses, often at the cost of safety. We further describe antigen targets and recent in vitro and in vivo results obtained to validate them. We finally discuss the use of MHC class II-restricted TCR in immunotherapy. Typically cellular anti-tumour immune responses have been attributed to CD8 T cells; however, we isolated mainly CD4 T cells. Importantly, these MHC class II-restricted TCRs have the potential to induce broad, long lasting immune responses that enable cancer control. The use of CD4 T cell-derived TCRs for adoptive immunotherapy has so far been limited and we will here discuss their therapeutic potential.

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Aryloxy Triester Phosphonamidates of Phosphoantigens Exhibit Favorable Stability and Potent Activation of Vγ9/Vδ2 T‐Cells

10.26434/chemrxiv.6755033.v1 ◽

2018 ◽

Cited By ~ 1

Author(s):

Hachemi Kadri ◽

Taher E. Taher ◽

Qin Xu ◽

Richard T. Bryan ◽

Benjamin E. Willcox ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Serum Stability ◽

T Cell Immune Responses ◽

Further Development

We previously reported the application of the aryloxy triester phosphoramidate prodrug technology to the phosphoantigen (E)-4-hydroxybut-2-enyl phosphate (HMBP). Although these prodrugs exhibited potent activation of Vγ9/Vδ2 T‐cell immune responses, their stability was low due to the rapid cleavage of the -O-P- bond. To address this, we herein report the application of the same prodrug strategy to two HMBP phosphonates, which have stable -CH2-P- or -CF2-P- bonds. These HMBP phosphonate prodrugs, phosphonamidates, exhibited excellent serum stability and potent activation of Vgama9/Vdelta2 T‐cells making them attractive compounds for further development as potential immunotherapeutics.

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Aryloxy Triester Phosphonamidates of Phosphoantigens Exhibit Favorable Stability and Potent Activation of Vγ9/Vδ2 T‐Cells

10.26434/chemrxiv.6755033 ◽

2018 ◽

Author(s):

Hachemi Kadri ◽

Taher E. Taher ◽

Qin Xu ◽

Richard T. Bryan ◽

Benjamin E. Willcox ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Serum Stability ◽

T Cell Immune Responses ◽

Further Development

We previously reported the application of the aryloxy triester phosphoramidate prodrug technology to the phosphoantigen (E)-4-hydroxybut-2-enyl phosphate (HMBP). Although these prodrugs exhibited potent activation of Vγ9/Vδ2 T‐cell immune responses, their stability was low due to the rapid cleavage of the -O-P- bond. To address this, we herein report the application of the same prodrug strategy to two HMBP phosphonates, which have stable -CH2-P- or -CF2-P- bonds. These HMBP phosphonate prodrugs, phosphonamidates, exhibited excellent serum stability and potent activation of Vgama9/Vdelta2 T‐cells making them attractive compounds for further development as potential immunotherapeutics.

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