scholarly journals Transporters Associated with Antigen Processing (TAP)-independent Presentation of Soluble Insulin to α/β T Cells by the Class Ib Gene Product, Qa-1b

1998 ◽  
Vol 188 (5) ◽  
pp. 961-971 ◽  
Author(s):  
S. Mark Tompkins ◽  
Jennifer R. Kraft ◽  
Chinh T. Dao ◽  
Mark J. Soloski ◽  
Peter E. Jensen
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Antigen Processing ◽  
Mhc Class Ib ◽  
Histocompatibility Complex ◽  
Soluble Insulin ◽  
Restriction Element ◽  
Antigen Presenting ◽  
Different Tissues ◽  
Class Ib

T cell hybridomas isolated from nonresponder H-2b mice immunized with pork insulin were stimulated by insulin in the presence of major histocompatibility complex (MHC)-unmatched antigen presenting cells. The restriction element used by these CD4− T cells was mapped to an oligomorphic MHC class Ib protein encoded in the T region and identified as Qa-1b using transfectants. The antigenic determinant was localized to the insulin B chain, and experiments with truncated peptides suggested that it is unexpectedly long, comprising most or all of the 30 amino acid B chain. The antigen processing pathway used to present insulin to the Qa-1b– restricted T cells does not require transporters associated with antigen processing (TAP), and it is inhibited by chloroquine. A wide variety of cell lines from different tissues efficiently present soluble insulin to Qa-1b–restricted T cells, and insulin presentation is not enhanced by phagocytic stimuli. Our results demonstrate that Qa-1b can function to present exogenous protein to T cells in a manner similar to MHC class II molecules. Therefore, this class Ib protein may have access to a novel antigen processing pathway that is not available to class Ia molecules.

scholarly journals The Selection of M3-Restricted T Cells Is Dependent on M3 Expression and Presentation of N-Formylated Peptides in the Thymus

1999 ◽  
Vol 190 (12) ◽  
pp. 1869-1878 ◽  
Author(s):  
Nancy M. Chiu ◽  
Bin Wang ◽  
Kristen M. Kerksiek ◽  
Roger Kurlander ◽  
Eric G. Pamer ◽  
...  
Keyword(s):  
T Cells ◽  
Negative Selection ◽  
Antigen Processing ◽  
Partial Agonist ◽  
Mhc Class Ib ◽  
Histocompatibility Complex ◽  
Fetal Thymic Organ Culture ◽  
Single Positive ◽  
Class Ib

The major histocompatibility complex (MHC) class Ib molecule H2-M3 binds N-formylated peptides from mitochondria and bacteria. To explore the role of M3 expression and peptide supply in positive and negative selection, we generated transgenic mice expressing an M3-restricted TCR-α/β from a CD8+ T cell hybridoma (D7) specific for a listerial peptide (LemA). Development of M3-restricted transgenic T cells is impaired in both β2-microglobulin–deficient and transporter associated with antigen processing (TAP)-deficient mice, but is not diminished by changes in the H-2 haplotype. Maturation of M3/LemA-specific CD8+ single positive cells in fetal thymic organ culture was sensitive to M3 expression levels as determined by antibody blocking and use of the castaneus mutant allele of M3. Positive selection was rescued in TAP−/− lobes by nonagonist mitochondrial and bacterial peptides, whereas LemA and a partial agonist variant caused negative selection. Thus, M3-restricted CD8+ T cells are positively and negatively selected by M3, with no contribution from the more abundant class Ia molecules. These results demonstrate that class Ib molecules can function in thymic education like class Ia molecules, despite limited ligand diversity and low levels of expression.

Mechanism of Action of Antimalarial Drugs: Inhibition of Antigen Processing and Presentation

Lupus ◽  
1993 ◽  
Vol 2 (1_suppl) ◽  
pp. 9-12 ◽  
Author(s):  
Robert I. Fox ◽  
Ho-Il Kang
Keyword(s):  
T Cells ◽  
Endoplasmic Reticulum ◽  
Cell Surface ◽  
Mhc Class Ii ◽  
Antigen Processing ◽  
Antigenic Peptides ◽  
Underlying Basis ◽  
Peptide Complexes ◽  
Antigen Presenting ◽  
Antimalarial Compounds

Recent studies have elucidated the steps involved in the association of antigenic peptides with major histocompatibility complex (MHC) encoded proteins and have suggested how antimalarial compounds might influence this important site of immune activation. These steps of antigen presentation in the macrophage (or other antigen-presenting cells) include: (a) the partial proteolytic degradation of endogenous and exogenous proteins into peptides within the lysosome; (b) the synthesis of MHC class II (i.e. HLA-D associated) α, β, and invariant (Ii) chains in the endoplasmic reticulum; (c) the initial association of α-Ii and β-li chains in the endoplasmic reticulum and the transport of these complexes to the primary endosome; (d) the fusion of lysosomal vacuoles and endosomal vacuoles, allowing the mixtures of lysosomal enzymes, peptides, α–Ii and β–Ii; (e) the displacement of Ii chains by peptides to form α–β–peptide complexes in the endosome; and (f) the migration of α–β–peptide complexes to the macrophage cell surface where they can stimulate CD4 T cells, resulting in release of cytokines. A low pH is required for digestion of the protein by acidic hydrolases in the lysosome, for assembly of the α–β–peptide complex and for its transport to the cell surface. Chloroquine and hydroxychloroquine are weak diprotic bases that can diffuse across the cell membrane and raise the pH within cell vesicles. This background provides the underlying basis for the theory that antimalarials may act to prevent autoimmunity by the following putative mechanism. Antimalarial compounds may: (a) stabilize the α-Ii and β-Ii interactions and prevent low-affinity peptides from forming α–β–peptide complexes; and (b) interfere with the efficient movement of α-Ii, β-Ii and α–β–peptide complexes to the correct locations within the cell cytoplasm or to the cell surfaces. Decreased presentation of autoantigenic peptides by macrophages might then lead to downregulation of autoimmune CD4+ T cells and diminish release of cytokines associated with clinical and laboratory signs of autoimmune disease.

scholarly journals Presentation of Toxoplasma gondii Antigens via the Endogenous Major Histocompatibility Complex Class I Pathway in Nonprofessional and Professional Antigen-Presenting Cells

2007 ◽  
Vol 75 (11) ◽  
pp. 5200-5209 ◽  
Author(s):  
Florence Dzierszinski ◽  
Marion Pepper ◽  
Jason S. Stumhofer ◽  
David F. LaRosa ◽  
Emma H. Wilson ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Antigen Processing ◽  
Cell Types ◽  
T Cell Response ◽  
Complex Class ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Antigen Presenting

ABSTRACT Challenge with the intracellular protozoan parasite Toxoplasma gondii induces a potent CD8+ T-cell response that is required for resistance to infection, but many questions remain about the factors that regulate the presentation of major histocompatibility complex class I (MHC-I)-restricted parasite antigens and about the role of professional and nonprofessional accessory cells. In order to address these issues, transgenic parasites expressing ovalbumin (OVA), reagents that track OVA/MHC-I presentation, and OVA-specific CD8+ T cells were exploited to compare the abilities of different infected cell types to stimulate CD8+ T cells and to define the factors that contribute to antigen processing. These studies reveal that a variety of infected cell types, including hematopoietic and nonhematopoietic cells, are capable of activating an OVA-specific CD8+ T-cell hybridoma, and that this phenomenon is dependent on the transporter associated with antigen processing and requires live T. gondii. Several experimental approaches indicate that T-cell activation is a consequence of direct presentation by infected host cells rather than cross-presentation. Surprisingly, nonprofessional antigen-presenting cells (APCs) were at least as efficient as dendritic cells at activating this MHC-I-restricted response. Studies to assess whether these cells are involved in initiation of the CD8+ T-cell response to T. gondii in vivo show that chimeric mice expressing MHC-I only in nonhematopoietic compartments are able to activate OVA-specific CD8+ T cells upon challenge. These findings associate nonprofessional APCs with the initial activation of CD8+ T cells during toxoplasmosis.

scholarly journals Lethal murine graft-versus-host disease induced by donor gamma/delta expressing T cells with specificity for host nonclassical major histocompatibility complex class Ib antigens

Blood ◽  
1996 ◽  
Vol 87 (2) ◽  
pp. 827-837 ◽  
Author(s):  
BR Blazar ◽  
PA Taylor ◽  
A Panoskaltsis-Mortari ◽  
TA Barrett ◽  
JA Bluestone ◽  
...  
Keyword(s):  
T Cells ◽  
Gene Products ◽  
Mhc Class Ib ◽  
Gamma Delta ◽  
Graft Versus Host ◽  
Histocompatibility Complex ◽  
Delta Cell ◽  
Delta Cells ◽  
Class Ib ◽  
Gamma Delta Cells

Although T-cell receptor (TCR) alpha/beta expressing cells have a well- known role in graft-versus-host disease (GVHD) generation, the role of TCR gamma/delta expressing cells in this process has remained unclear. To elucidate the potential function of TCR gamma/delta cells in GVHD, we have used transgenic (Tg) H-2d mice (termed G8) that express gamma/delta heterodimers on a high proportion of peripheral T cells. In vitro, G8 Tg gamma/delta T cells proliferate to and kill C57BL/6 (B6) (H-2b) which express gene products (T10b and T22b) from the nonclassical major histocompatibility complex (MHC) class Ib H-2T region. The infusion of G8 Tg (H-2Td) TCR gamma/delta cells into lethally irradiated [900 cGy total body irradiation (TBI)] B6 (H-2b) mice resulted in the generation of lethal GVHD characterized histologically by destruction of the spleen, liver, lung, and colon. Lethal GVHD was prevented by the injection of anti-TCR gamma/delta monoclonal antibodies. Immunohistochemical analysis of B6 recipients post-bone marrow transplantation (BMT) confirmed that G8 Tg TCR gamma/delta cells infiltrated GVHD target tissues (skin, liver, colon, and lung) and were absent in recipients treated with anti-TCR gamma/delta monoclonal antibodies (MoAbs) but not anti-CD4 plus anti- CD8 MoAbs. In contrast, injection of TCR gamma/delta+ cells into irradiated (900 cGy TBI) B6.A-TIaa BoyEg mice that do not express either T10b or T22b did not induce lethal GVHD. Similarly, in a different GVHD system in which sublethal irradiation without bone marrow (BM) rescue was used, B6 but not B6.A-TIaa/BoyEg mice were found to be susceptible to TCR gamma delta+ cell mediated GVHD-induced lethality characterized by an aplasia syndrome. These results demonstrate that TCR gamma/delta cells have the capacity to cause acute lethal GVHD in mice and suggest that nonclassical MHC class Ib gene products expressed on GVHD target organs are responsible for G8 Tg TCR gamma/delta+ cell mediated lethality.

scholarly journals Specific T Helper Cell Requirement for Optimal Induction of Cytotoxic T Lymphocytes against Major Histocompatibility Complex Class II Negative Tumors

1998 ◽  
Vol 187 (5) ◽  
pp. 693-702 ◽  
Author(s):  
Ferry Ossendorp ◽  
Erica Mengedé ◽  
Marcel Camps ◽  
Rian Filius ◽  
Cornelis J.M. Melief
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Protective Immunity ◽  
Class Ii ◽  
T Helper ◽  
Histocompatibility Complex ◽  
Helper Epitope ◽  
Antigen Presenting

This study shows that induction of tumor-specific CD4+ T cells by vaccination with a specific viral T helper epitope, contained within a synthetic peptide, results in protective immunity against major histocompatibility complex (MHC) class II negative, virus-induced tumor cells. Protection was also induced against sarcoma induction by acutely transforming retrovirus. In contrast, no protective immunity was induced by vaccination with an unrelated T helper epitope. By cytokine pattern analysis, the induced CD4+ T cells were of the T helper cell 1 type. The peptide-specific CD4+ T cells did not directly recognize the tumor cells, indicating involvement of cross-priming by tumor-associated antigen-presenting cells. The main effector cells responsible for tumor eradication were identified as CD8+ cytotoxic T cells that were found to recognize a recently described immunodominant viral gag-encoded cytotoxic T lymphocyte (CTL) epitope, which is unrelated to the viral env-encoded T helper peptide sequence. Simultaneous vaccination with the tumor-specific T helper and CTL epitopes resulted in strong synergistic protection. These results indicate the crucial role of T helper cells for optimal induction of protective immunity against MHC class II negative tumor cells. Protection is dependent on tumor-specific CTLs in this model system and requires cross-priming of tumor antigens by specialized antigen-presenting cells. Thus, tumor-specific T helper epitopes have to be included in the design of epitope-based vaccines.

scholarly journals Major histocompatibility complex class II-associated peptides control the presentation of bacterial superantigens to T cells.

1996 ◽  
Vol 183 (3) ◽  
pp. 1083-1092 ◽  
Author(s):  
R Wen ◽  
G A Cole ◽  
S Surman ◽  
M A Blackman ◽  
D L Woodland
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Antigen Processing ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Bacterial Superantigens ◽  
Toxic Shock Syndrome Toxin

Recent studies have shown that only a subset of major histocompatibility complex (MHC) class II molecules are able to present bacterial superantigens to T cells, leading to the suggestion that class-II associated peptides may influence superantigen presentation. Here, we have assessed the potential role of peptides on superantigen presentation by (a) analyzing the ability of superantigens to block peptide-specific T cell responses and (b) analyzing the ability of individual peptides to promote superantigen presentation on I-Ab-expressing T2 cells that have a quantitative defect in antigen processing. A series of peptides is described that specifically promote either toxic shock syndrome toxin (TSST) 1 or staphylococcal enterotoxin A (SEA) presentation. Whereas some peptides promoted the presentation of TSST-1 (almost 5,000-fold in the case of one peptide), other peptides promoted the presentation of SEA. These data demonstrate that MHC class II-associated peptides differentially influence the presentation of bacterial superantigens to T cells.

scholarly journals The Majority of H2-M3 Is Retained Intracellularly in a Peptide-Receptive State and Traffics to the Cell Surface in the Presence of N-Formylated Peptides

1999 ◽  
Vol 190 (3) ◽  
pp. 423-434 ◽  
Author(s):  
Nancy M. Chiu ◽  
Taehoon Chun ◽  
Miriam Fay ◽  
Manas Mandal ◽  
Chyung-Ru Wang
Keyword(s):  
Cell Surface ◽  
Antigen Processing ◽  
Cytotoxic T Cells ◽  
Antigen Presenting Cells ◽  
Cell Types ◽  
Surface Expression ◽  
Peptide Vaccination ◽  
Histocompatibility Complex ◽  
Antigen Presenting ◽  
Class Ib

We used a new monoclonal antibody (mAb 130) to analyze the intracellular trafficking and surface expression of H2-M3, the major histocompatibility complex class Ib molecule that presents N-formylated peptides to cytotoxic T cells. M3 surface expression is undetectable in most cell types due to the paucity of endogenous antigen. M3 is induced on the cell surface by addition of high-affinity N-formylated peptides from mitochondria and listeria. Peptide-induced M3 expression is most efficient on antigen presenting cells. Basal and inducible expression of M3 is transporter associated with antigen processing (TAP)-dependent, distinguishing M3 from the class Ib molecules TL and CD1. Unlike the expression of class Ia molecules and a previously described M3/Ld chimera, surface expression of M3 cannot be rescued by lowered temperature, suggesting that the α3 domain and transmembrane region of M3 may control trafficking. Pulse–chase analysis and use of trafficking inhibitors revealed a pool of empty M3 in the endoplasmic reticulum or early Golgi apparatus. Addition of exogenous peptide allows maturation with kinetics matching those of Dd. The lack of endogenous N-formylated peptide allows discovery of novel pathogen-derived peptides in normal antigen presenting cells. The nonpolymorphic nature of M3 and its ability to present bacterial antigens rapidly and dominantly make it an attractive target for peptide vaccination strategies.

scholarly journals Epithelial MHC class II directs microbiota-specific intestinal immune homeostasis

2022 ◽  
Author(s):  
Emily M Eshleman ◽  
Tzu-Yu Shao ◽  
Vivienne Woo ◽  
Taylor Rice ◽  
Jordan Whitt ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Intestinal Epithelial ◽  
Mhc Ii ◽  
Adult Mice ◽  
Histocompatibility Complex ◽  
Mucosal Tissues ◽  
T Cell Regulation ◽  
Antigen Presenting

Dysregulated immune responses to resident microbes promote pathologic inflammation, however, the mechanisms instructing commensal-specific T cells remain poorly understood. Here, we find that non-hematopoietic intestinal epithelial cells (IECs) represent the primary cells expressing major histocompatibility complex (MHC) II at the intestinal host-microbiota interface. Interestingly, epithelial MHCII and commensal-specific CD4+ T cells were concurrently induced by post-natal microbiota colonization, provoking the hypothesis that epithelial MHCII regulates local commensal-specific CD4+ T cells. While MHCII on classical antigen presenting cells directs expansion of antigen-specific CD4+ T cells, loss of IEC-intrinsic MHCII surprisingly led to elevated commensal-specific CD4+ T cells in the intestine. Further, epithelial MHCII expression actively limited accumulation of antigen-specific CD4+ T cells in adult mice. Expansion of commensal-specific Th17 cells was restricted by epithelial MHCII, and remarkably mice lacking epithelial MHCII were highly susceptible to microbiota-triggered inflammation. Collectively, these data indicate that impaired epithelial MHCII-T cell regulation within mucosal tissues alters microbiota-specific immunity and predisposes to chronic inflammation.

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