Nonclassical MHC class Ib–restricted cytotoxic T cells monitor antigen processing in the endoplasmic reticulum

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.

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

Journal of Experimental Medicine ◽

10.1084/jem.188.5.961 ◽

1998 ◽

Vol 188 (5) ◽

pp. 961-971 ◽

Cited By ~ 41

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.

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Faculty Opinions recommendation of Direct recognition by alphabeta cytolytic T cells of Hfe, a MHC class Ib molecule without antigen-presenting function.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1027869.343646 ◽

2005 ◽

Author(s):

Seiamak Bahram

Keyword(s):

T Cells ◽

Mhc Class Ib ◽

Antigen Presenting ◽

Direct Recognition ◽

Class Ib

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Faculty Opinions recommendation of Direct recognition by alphabeta cytolytic T cells of Hfe, a MHC class Ib molecule without antigen-presenting function.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1027869.334844 ◽

2005 ◽

Author(s):

Peter Van Endert

Keyword(s):

T Cells ◽

Mhc Class Ib ◽

Antigen Presenting ◽

Direct Recognition ◽

Class Ib

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

Lupus ◽

10.1177/0961203393002001031 ◽

1993 ◽

Vol 2 (1_suppl) ◽

pp. 9-12 ◽

Cited By ~ 29

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.

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Impaired response to Listeria in H2-M3–deficient mice reveals a nonredundant role of MHC class Ib–specific T cells in host defense

Journal of Experimental Medicine ◽

10.1084/jem.20051866 ◽

2006 ◽

Vol 203 (2) ◽

pp. 449-459 ◽

Cited By ~ 38

Author(s):

Honglin Xu ◽

Taehoon Chun ◽

Hak-Jong Choi ◽

Bin Wang ◽

Chyung-Ru Wang

Keyword(s):

T Cells ◽

T Cell ◽

Host Defense ◽

Cd8 T Cells ◽

Mhc Class Ib ◽

Cell Responses ◽

Mhc Class Ia ◽

Deficient Mice ◽

Class Ib

The major histocompatibility complex (MHC) class Ib molecule H2-M3 primes the rapid expansion of CD8+ T cells by presenting N-formylated bacterial peptides. However, the significance of H2-M3–restricted T cells in host defense against bacteria is unclear. We generated H2-M3–deficient mice to investigate the role of H2-M3 in immunity against Listeria monocytogenes (LM), a model intracellular bacterial pathogen. H2-M3–deficient mice are impaired in early bacterial clearance during primary infection, with diminished LM-specific CD8+ T cell responses and compromised innate immune functions. Although H2-M3–restricted CD8+ T cells constitute a significant proportion of the anti-listerial CD8+ T cell repertoire, the kinetics and magnitude of MHC class Ia–restricted T cell responses are not altered in H2-M3–deficient mice. The fact that MHC class Ia–restricted responses cannot compensate for the H2-M3–mediated immunity suggests a nonredundant role of H2-M3 in the protective immunity against LM. Thus, the early H2-M3–restricted response temporally bridges the gap between innate and adaptive immune responses, subsequently affecting the function of both branches of the immune system.

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Qa-2–Dependent Selection of Cd8α/α T Cell Receptor α/β+ Cells in Murine Intestinal Intraepithelial Lymphocytes

Journal of Experimental Medicine ◽

10.1084/jem.192.10.1521 ◽

2000 ◽

Vol 192 (10) ◽

pp. 1521-1528 ◽

Cited By ~ 37

Author(s):

Gobardhan Das ◽

Dina S. Gould ◽

Mathew M. Augustine ◽

Gladis Fragoso ◽

Edda Scitto ◽

...

Keyword(s):

T Cells ◽

Mhc Class I ◽

Antigen Processing ◽

Intraepithelial Lymphocytes ◽

Class I ◽

Β Cells ◽

Double Knockout ◽

Intestinal Intraepithelial Lymphocytes ◽

Mhc Class I Molecule ◽

Nonclassical Mhc

Murine intestinal intraepithelial lymphocytes (iIELs) are made up of a heterogeneous mix of T cells with unique phenotypes. Whereas CD8+ T cells in peripheral lymphoid organs use CD8α/β and are selected on MHC class Ia molecules, a majority of iIELs use CD8α/α. Here, we report that the presence of CD8α/α TCR-α/β cells in iIELs is independent of classical MHC class I molecules Kb and Db, as illustrated by their presence in Kb/Db double-knockout mice and in mice lacking a nonclassical MHC class I molecule, CD1d. Most strikingly, their presence is decreased by ∼70% in mice lacking transporter associated with antigen processing (TAP). The TAP-dependent nonclassical MHC class I molecule Qa-2 is strongly implicated in the presence of these cells, as inferred from the low numbers of CD8α/α TCR-α/β T cells in mice deficient in Qa-2 genes. Second, a Qa-2–transgenic mouse made in a Qa-2− strain showed an increase in the numbers of CD8α/α cells among its iIELs. Thus, the presence of CD8α/α TCR-α/β cells in iIELs is mainly dependent on the nonclassical MHC class I molecule Qa-2.

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