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

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.

Download Full-text

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.

Download Full-text

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 ◽

10.1182/blood.v87.2.827.bloodjournal872827 ◽

1996 ◽

Vol 87 (2) ◽

pp. 827-837 ◽

Cited By ~ 31

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.

Download Full-text

An MHC class Ib–restricted CD8 T cell response confers antiviral immunity

Journal of Experimental Medicine ◽

10.1084/jem.20080570 ◽

2008 ◽

Vol 205 (7) ◽

pp. 1647-1657 ◽

Cited By ~ 26

Author(s):

Phillip A. Swanson ◽

Christopher D. Pack ◽

Annette Hadley ◽

Chyung-Ru Wang ◽

Iwona Stroynowski ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response ◽

Mhc Class Ib ◽

Wild Type ◽

Mhc Class Ia ◽

Class Ib

Although immunity against intracellular pathogens is primarily provided by CD8 T lymphocytes that recognize pathogen-derived peptides presented by major histocompatibility complex (MHC) class Ia molecules, MHC class Ib–restricted CD8 T cells have been implicated in antiviral immunity. Using mouse polyoma virus (PyV), we found that MHC class Ia–deficient (Kb−/−Db−/−) mice efficiently control this persistently infecting mouse pathogen. CD8 T cell depletion mitigates clearance of PyV in Kb−/−Db−/− mice. We identified the ligand for PyV-specific CD8 T cells in Kb−/−Db−/− mice as a nonamer peptide from the VP2 capsid protein presented by Q9, a member of the β2 microglobulin–associated Qa-2 family. Using Q9-VP2 tetramers, we monitored delayed but progressive expansion of these antigen-specific CD8αβ T cells in Kb−/−Db−/− mice. Importantly, we demonstrate that Q9-VP2–specific CD8 T cells more effectively clear wild-type PyV than a VP2 epitopenull mutant PyV. Finally, we show that wild-type mice also generate Q9-restricted VP2 epitope–specific CD8 T cells to PyV infection. To our knowledge, this is the first evidence for a defined MHC class Ib–restricted antiviral CD8 T cell response that contributes to host defense. This study motivates efforts to uncover MHC class Ib–restricted CD8 T cell responses in other viral infections, and given the limited polymorphism of MHC class Ib molecules, it raises the possibility of developing peptide-based viral vaccines having broad coverage across MHC haplotypes.

Download Full-text

A Population of Murine T Cells That Recognize an Inducible MHC Class Ib Molecule

Science ◽

10.1126/science.287.5451.314 ◽

2000 ◽

Vol 287 (5451) ◽

pp. 314-316 ◽

Cited By ~ 136

Author(s):

M. P. Crowley

Keyword(s):

T Cells ◽

Mhc Class Ib ◽

Class Ib

Download Full-text

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

Nature Immunology ◽

10.1038/ni.2282 ◽

2012 ◽

Vol 13 (6) ◽

pp. 579-586 ◽

Cited By ~ 46

Author(s):

Niranjana A Nagarajan ◽

Federico Gonzalez ◽

Nilabh Shastri

Keyword(s):

T Cells ◽

Endoplasmic Reticulum ◽

Antigen Processing ◽

Cytotoxic T Cells ◽

Mhc Class Ib ◽

Nonclassical Mhc ◽

Class Ib

Download Full-text

H2-M3–restricted CD8+ T cells are not required for MHC class Ib–restricted immunity against Listeria monocytogenes

Journal of Experimental Medicine ◽

10.1084/jem.20052256 ◽

2006 ◽

Vol 203 (2) ◽

pp. 383-391 ◽

Cited By ~ 8

Author(s):

Sarah E.F. D'Orazio ◽

Christine A. Shaw ◽

Michael N. Starnbach

Keyword(s):

T Cells ◽

Listeria Monocytogenes ◽

Cd8 T Cells ◽

T Cell Response ◽

Mhc Class Ib ◽

Wild Type ◽

Histocompatibility Complex ◽

Mutant Strains ◽

Antigen Presenting ◽

Deficient Mice

Studies using major histocompatibility complex (MHC)-Ia–deficient mice have shown that MHC-Ib–restricted CD8+ T cells can clear infections caused by intracellular pathogens such as Listeria monocytogenes. M3-restricted CD8+ T cells, which recognize short hydrophobic N-formylated peptides, appear to comprise a substantial portion of the MHC-Ib–restricted T cell response in the mouse model of L. monocytogenes infection. In this study, we isolated formyltransferase (fmt) mutant strains of L. monocytogenes that lacked the ability to add formyl groups to nascent polypeptides. These fmt mutant Listeria strains did not produce antigens that could be recognized by M3-restricted T cells. We showed that immunization of MHC-Ia–deficient mice with fmt mutant Listeria resulted in stimulation of a protective memory response that cleared subsequent challenge with wild-type L. monocytogenes, despite the fact that M3-restricted CD8+ T cells did not proliferate in these mice. These data suggest that M3-restricted T cells are not required for protection against L. monocytogenes and underscore the importance of searching for new antigen-presenting molecules among the large MHC-Ib family of proteins.

Download Full-text