scholarly journals Melanoma-Derived Extracellular Vesicles Bear the Potential for the Induction of Antigen-Specific Tolerance

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 665 ◽  
Author(s):  
Markus Düchler ◽  
Liliana Czernek ◽  
Lukasz Peczek ◽  
Wojciech Cypryk ◽  
Malgorzata Sztiller-Sikorska ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Tolerance Induction ◽  
Antigen Specificity ◽  
Activation Markers ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Suppressive Phenotype ◽  
Antigen Presenting ◽  
Specific Tolerance ◽  
Mixed Lymphocyte Reactions

Background: Cancer-induced immunosuppression is antigen-specific rather than systemic and the mechanisms for the antigen specificity are incompletely understood. Here we explore the option that tumor-associated antigens (TAAs) may be transferred to antigen-presenting cells (APCs), together with immunosuppressive molecules, through cancer-derived small extracellular vesicles (sEVs), such as exosomes. Stimulation of a suppressive phenotype in the very same APCs that take up TAAs may yield antigen-specific tolerance. Methods: sEVs isolated from patient-derived or well-established melanoma cell lines were used to demonstrate the transfer of major histocompatibility complex (MHC) molecules to the surface of APCs. The immunosuppressive influence of sEVs was assessed by flow cytometry analysis of activation markers, cytokine expression, and mixed lymphocyte reactions. Results: MHC class I molecules were transferred from melanoma cells to the cell surface of APCs by sEVs. Concomitantly, CD86 and CD40 co-stimulatory molecules were down-regulated and IL-6 production was strongly induced. TGF-β transported by sEVs contributed to the promotion of a suppressive phenotype of APCs. Conclusion: The presented results indicate the existence of a hitherto undescribed mechanism that offers an explanation for antigen-specific tolerance induction mediated by cancer-derived sEVs.

scholarly journals Liver Transplant Tolerance and Its Application to the Clinic: Can We Exploit the High Dose Effect?

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Eithne C. Cunningham ◽  
Alexandra F. Sharland ◽  
G. Alex Bishop
Keyword(s):  
Liver Transplant ◽  
Tolerance Induction ◽  
Experimental Models ◽  
Dose Effect ◽  
Liver Graft ◽  
High Dose ◽  
Transplant Tolerance ◽  
Tissue Mass ◽  
Mhc Molecules ◽  
Specific Tolerance

The tolerogenic properties of the liver have long been recognised, especially in regard to transplantation. Spontaneous acceptance of liver grafts occurs in a number of experimental models and also in a proportion of clinical transplant recipients. Liver graft acceptance results from donor antigen-specific tolerance, demonstrated by the extension of tolerance to other grafts of donor origin. A number of factors have been proposed to be involved in liver transplant tolerance induction, including the release of soluble major histocompatibility (MHC) molecules from the liver, its complement of immunosuppressive donor leucocytes, and the ability of hepatocytes to directly interact with and destroy antigen-specific T cells. The large tissue mass of the liver has also been suggested to act as a cytokine sink, with the potential to exhaust the immune response. In this review, we outline the growing body of evidence, from experimental models and clinical transplantation, which supports a role for large tissue mass and high antigen dose in the induction of tolerance. We also discuss a novel gene therapy approach to exploit this dose effect and induce antigen-specific tolerance robust enough to overcome a primed T cell memory response.

scholarly journals Inherent reactivity of unselected TCR repertoires to peptide-MHC molecules

2019 ◽  
Vol 116 (44) ◽  
pp. 22252-22261 ◽  
Author(s):  
S. Harsha Krovi ◽  
John W. Kappler ◽  
Philippa Marrack ◽  
Laurent Gapin
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Selective Pressure ◽  
Dominant Role ◽  
Antigen Receptors ◽  
Complex Molecules ◽  
Peptide Antigens ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Antigen Presenting

The repertoire of αβ T cell antigen receptors (TCRs) on mature T cells is selected in the thymus where it is rendered both self-tolerant and restricted to the recognition of major histocompatibility complex molecules presenting peptide antigens (pMHC). It remains unclear whether germline TCR sequences exhibit an inherent bias to interact with pMHC prior to selection. Here, we isolated TCR libraries from unselected thymocytes and upon reexpression of these random TCR repertoires in recipient T cell hybridomas, interrogated their reactivities to antigen-presenting cell lines. While these random TCR combinations could potentially have reacted with any surface molecule on the cell lines, the hybridomas were stimulated most frequently by pMHC ligands. The nature and CDR3 loop composition of the TCRβ chain played a dominant role in determining pMHC-reactivity. Replacing the germline regions of mouse TCRβ chains with those of other jawed vertebrates preserved reactivity to mouse pMHC. Finally, introducing the CD4 coreceptor into the hybridomas increased the proportion of cells that could respond to pMHC ligands. Thus, αβ TCRs display an intrinsic and evolutionary conserved bias for pMHC molecules in the absence of any selective pressure, which is further strengthened in the presence of coreceptors.

scholarly journals Donor major histocompatibility complex (MHC) peptides are presented by recipient MHC molecules during graft rejection.

1992 ◽  
Vol 175 (1) ◽  
pp. 305-308 ◽  
Author(s):  
G Benichou ◽  
P A Takizawa ◽  
C A Olson ◽  
M McMillan ◽  
E E Sercarz
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Critical Role ◽  
Major Histocompatibility ◽  
Skin Allograft ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Molecular Therapies ◽  
Antigen Presenting

Peptides from donor major histocompatibility complex (MHC) molecules were examined for their activation of allogeneically primed T cells. After immunization with either allogeneic spleen cells or a skin allograft, primed T cells proliferate in response to peptides derived from polymorphic regions of alpha and beta chains of class II allo-MHC molecules. The results demonstrate that presentation of donor-MHC peptides by host-derived antigen-presenting cells is a common event in vivo. Thus, self-restricted T cell recognition of processed alloantigens may play a critical role in transplantation. An in-depth understanding of this response may result in the development of additional molecular therapies to combat allograft rejection.

scholarly journals Presence and regulation of messenger ribonucleic acids encoding components of the class II major histocompatibility complex-associated antigen processing pathway in the bovine corpus luteum

Reproduction ◽  
2006 ◽  
Vol 131 (4) ◽  
pp. 689-698 ◽  
Author(s):  
Matthew J Cannon ◽  
John S Davis ◽  
Joy L Pate
Keyword(s):  
Corpus Luteum ◽  
Estrous Cycle ◽  
Antigen Processing ◽  
Class Ii ◽  
Luteal Cells ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Class Ii Mhc ◽  
Luteal Tissue ◽  
Antigen Presenting

Luteal cells express class II major histocompatibility complex (MHC) molecules and can stimulate T lymphocyte proliferationin vitro. However, it is unknown whether luteal cells express the intracellular components necessary to process the peptides presented by class II MHC molecules. The objective of the present study was to examine the expression and regulation of three major class II-associated antigen processing components – class II MHC-associated invariant chain (Ii), DMα and DMβ – in luteal tissue. Corpora lutea were collected early in the estrous cycle, during midcycle and late in the estrous cycle, and at various times following administration of a luteolytic dose of prostaglandin F2α(PGF2α) to the cow. Northern analysis revealed the presence of mRNA encoding each of the class II MHC-associated antigen processing proteins in luteal tissue. Ii mRNA concentrations did not change during the estrous cycle, whereas DMα and DMβ mRNA concentrations were highest in midcycle luteal tissue compared with either early or late luteal tissue. Tumor necrosis factor-α (TNF-α) reduced DMα mRNA concentrations in cultured luteal cells in the presence of LH or PGF2α. DMα and DMβ mRNA were also present in highly enriched cultures of luteal endothelial (CLENDO) cells, and DMα mRNA concentrations were greater in CLENDO cultures compared with mixed luteal cell cultures. Expression of invariant chain, DMα and DMβ genes indicates that cells within the corpus luteum express the minimal requirements to act as functional antigen-presenting cells, and the observation that CLENDO cells are a source of DMα and DMβ mRNA indicates that non-immune cells within the corpus luteum may function as antigen-presenting cells.

scholarly journals Endogenous and Exogenous CD1-Binding Glycolipids

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Janice M. H. Cheng ◽  
Ashna A. Khan ◽  
Mattie S. M. Timmer ◽  
Bridget L. Stocker
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Major Histocompatibility Complex ◽  
Cell Surface ◽  
Intracellular Trafficking ◽  
Antigen Presenting Cells ◽  
Peptide Antigens ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Antigen Presenting

In the same way that peptide antigens are presented by major histocompatibility complex (MHC) molecules, glycolipid antigens can also activate the immune response via binding to CD1 proteins on antigen-presenting cells (APCs) and stimulate CD1-restricted T cells. In humans, there are five members of the CD1 family, termed CD1a–e, of which CD1a–d are involved in glycolipid presentation at the cell surface, while CD1e is involved in the intracellular trafficking of glycolipid antigens. Both endogenous (self-derived) and exogenous (non-self-derived) glycolipids have been shown to bind to members of the CD1 family with varying degrees of specificity. In this paper we focus on the key glycolipids that bind to the different members of the CD1 family.

scholarly journals Role of BoLA-DRB3 genetic diversity against resistance to mastitis in cattle: Review

2019 ◽  
pp. 30-36 ◽  
Author(s):  
Namita Kumari ◽  
Shubham Loat ◽  
Shallu Saini ◽  
Nitika Dhilor ◽  
Anurag Kumar ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Immune Response ◽  
Major Histocompatibility Complex ◽  
Immune Regulation ◽  
Peptide Antigens ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Antigen Presenting ◽  
Jawless Fish

The major histocompatibility complex (MHC) is an organized cluster of tightly linked genes, present in all vertebrates, playing an important role in the immune system, except the jawless fish [1]. MHC was first identified during tissue transplantation studies in mice [2] and was first known for its role in histocompatibility. Consequently, the role of MHC was discovered in immune regulation [3] and several other functions [4,5]. The important function of the MHC is to code for specialized antigen-presenting receptor glycoproteins, also called as MHC molecules. The products of these genes are involved in the induction and regulation of immune response. These molecules bind processed peptide antigens and present them to T-lymphocytes, thereby triggering immune response.

scholarly journals Molecular Recognition of Lipid Antigens by T Cell Receptors

1999 ◽  
Vol 189 (1) ◽  
pp. 195-205 ◽  
Author(s):  
Ethan P. Grant ◽  
Massimo Degano ◽  
Jean-Pierre Rosat ◽  
Steffen Stenger ◽  
Robert L. Modlin ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptors ◽  
Antigen Specificity ◽  
Peptide Antigen ◽  
Lipid Antigens ◽  
Peptide Antigens ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Lipid Antigen ◽  
Binding Groove

The T cell antigen receptor (TCR) mediates recognition of peptide antigens bound in the groove of major histocompatibility complex (MHC) molecules. This dual recognition is mediated by the complementarity-determining residue (CDR) loops of the α and β chains of a single TCR which contact exposed residues of the peptide antigen and amino acids along the MHC α helices. The recent description of T cells that recognize hydrophobic microbial lipid antigens has challenged immunologists to explain, in molecular terms, the nature of this interaction. Structural studies on the murine CD1d1 molecule revealed an electrostatically neutral putative antigen-binding groove beneath the CD1 α helices. Here, we demonstrate that α/β TCRs, when transferred into TCR-deficient recipient cells, confer specificity for both the foreign lipid antigen and CD1 isoform. Sequence analysis of a panel of CD1-restricted, lipid-specific TCRs reveals the incorporation of template-independent N nucleotides that encode diverse sequences and frequent charged basic residues at the V(D)J junctions. These sequences permit a model for recognition in which the TCR CDR3 loops containing charged residues project between the CD1 α helices, contacting the lipid antigen hydrophilic head moieties as well as adjacent CD1 residues in a manner that explains antigen specificity and CD1 restriction.

scholarly journals Hapten-specific T cell lines mediating delayed hypersensitivity to contact-sensitizing agents.

1982 ◽  
Vol 156 (1) ◽  
pp. 300-305 ◽  
Author(s):  
W R Thomas ◽  
P L Mottram ◽  
J F Miller
Keyword(s):  
Major Histocompatibility Complex ◽  
Specific Antigen ◽  
Delayed Hypersensitivity ◽  
Antigen Specificity ◽  
Continuous Cultures ◽  
Histocompatibility Complex ◽  
Picryl Chloride ◽  
T Cell Lines ◽  
Antigen Presenting ◽  
Proliferation Assays

Continuous cultures of T cells from the lymph nodes of mice sensitized to the contact sensitizers 4-ethoxymethylene-2-phenyl oxazolone or picryl chloride have been established. For continuous proliferation, the lines required specific antigen, syngeneic antigen-presenting cells, and growth factors from the supernatant of concanavalin-A-stimulated lymphoid cultures. Cells from the lines showed antigen specificity and major histocompatibility complex restriction in proliferation assays and in delayed hypersensitivity. They could mediate delayed hypersensitivity to the sensitizer presented as a reactive hapten or coupled to keyhold limpet hemocyanin.

Dissociation of thymic positive and negative selection in transgenic mice expressing major histocompatibility complex class I molecules exclusively on thymic cortical epithelial cells

Blood ◽  
2001 ◽  
Vol 97 (5) ◽  
pp. 1336-1342 ◽  
Author(s):  
Myriam Capone ◽  
Paola Romagnoli ◽  
Friedrich Beermann ◽  
H. Robson MacDonald ◽  
Joost P. M. van Meerwijk
Keyword(s):  
Major Histocompatibility Complex ◽  
Transgenic Mice ◽  
Mhc Class I ◽  
Negative Selection ◽  
Tolerance Induction ◽  
Antigen Presenting Cells ◽  
Class I ◽  
Histocompatibility Complex ◽  
Antigen Presenting ◽  
Peptide Interaction

Thymic positive and negative selection of developing T lymphocytes confronts us with a paradox: How can a T-cell antigen receptor (TCR)-major histocompatibility complex (MHC)/peptide interaction in the former process lead to transduction of signals allowing for cell survival and in the latter induce programmed cell death or a hyporesponsive state known as anergy? One of the hypotheses put forward states that the outcome of a TCR-MHC/peptide interaction depends on the cell type presenting the selecting ligand to the developing thymocyte. Here we describe the development and lack of self-tolerance of CD8+ T lymphocytes in transgenic mice expressing MHC class I molecules in the thymus exclusively on cortical epithelial cells. Despite the absence of MHC class I expression on professional antigen-presenting cells, normal numbers of CD8+ cells were observed in the periphery. Upon specific activation, transgenic CD8+ T cells efficiently lysed syngeneic MHC class I+ targets in vitro and in vivo, indicating that thymic cortical epithelium (in contrast to medullary epithelium and antigen-presenting cells of hematopoietic origin) is incapable of tolerance induction. Thus, compartmentalization of the antigen-presenting cells involved in thymic positive selection and tolerance induction can (at least in part) explain the positive/negative selection paradox.

Antigen-presenting cells and tolerance induction

Allergy ◽  
2002 ◽  
Vol 57 (1) ◽  
pp. 2-8 ◽  
Author(s):  
D. von Bubnoff ◽  
H. de la Salle ◽  
J. Wessendorf ◽  
S. Koch ◽  
D. Hanau ◽  
...  
Keyword(s):  
Tolerance Induction ◽  
Antigen Presenting Cells ◽  
Antigen Presenting
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