The Role of Structurally Conserved Class I MHC in Tumor Rejection: Contribution of the Q8 Locus

Chiang, Eugene Y.; Stroynowski, Iwona

doi:10.4049/jimmunol.177.4.2123

Cited by 8 publications

(6 citation statements)

References 47 publications

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“…This class Ib molecule predominantly assembles with a peptide derived from the leader sequence of class Ia molecules, H2-D and L. However, Qa-1 also has the capacity to present a variety of self and foreign peptides to TCRαβ T cells (14–18). Qa-2 (encoded by H2-Q6 , - Q7 , - Q8 , and - Q9 ) assembles with a highly diverse repertoire of endogenous peptides sharing a common peptide-binding motif (19) and functions as an antigen-presenting molecule in tumor immunity (20). H2-M3 selectively binds and presents N -formylated bacterial and mitochondrial peptides to CD8+ T cells (2, 21).…”

Section: Introductionmentioning

confidence: 99%

An MHC Class Ib-Restricted CD8+ T Cell Response to Lymphocytic Choriomeningitis Virus

Chen

Jay

Fairbanks

et al. 2011

The Journal of Immunology

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Conventional MHC class Ia-restricted CD8+ T cells play a dominant role in the host response to virus infections but recent studies indicate that T cells with specificity for nonclassical MHC class Ib molecules may also participate in host defense. To investigate the potential role of class Ib molecules in anti-viral immune responses, Kb−/−Db−/−CIITA−/− mice lacking expression of MHC class Ia and class II molecules were infected with LCMV. These animals have a large class Ib-selected CD8+ T cell population and they were observed to mediate partial (but incomplete) virus clearance during acute LCMV infection as compared to Kb−/−Db−/−®2M−/− mice that lack expression of both MHC class Ia and class Ib molecules. Infection was associated with expansion of splenic CD8+ T cells and induction of granzyme B and IFN© effector molecules in CD8+ T cells. Partial virus clearance was dependent on CD8〈®+ cells. In vitro T cell re-stimulation assays demonstrated induction of a population of ®2M-dependent, MHC class Ib-restricted CD8+ T cells with specificity for viral antigen(s) and a yet to be defined nonclassical MHC molecule(s). MHC class Ib-restricted CD8+ T cell responses were also observed after infection of Kb−/−Db−/− mice, despite the low number of CD8+ T cells in these animals. Long term infection studies demonstrated chronic infection and gradual depletion of CD8+ T cells in Kb−/−Db−/−CIITA−/− mice, demonstrating that class Ia molecules are required for viral clearance. These findings demonstrate that class Ib-restricted CD8+ T cells have the potential to participate in the host immune response to LCMV.

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Section: Introductionmentioning

confidence: 99%

An MHC Class Ib-Restricted CD8+ T Cell Response to Lymphocytic Choriomeningitis Virus

Chen

Jay

Fairbanks

et al. 2011

The Journal of Immunology

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“…BMDC were infected with LM 4 h before each assay as described above. For blocking experiments, LM-infected BMDC were preincubated with mouse IgG or mAb against CD1d (3H3, in house)(58), H2-M3 (130, in house) (7), MR1 (26.5) (4), Qa-1 b (6A8.6F10.1A6, ATCC) (31, 59), and Qa-2 (M46) (60) for 30 min at 37 °C prior to assay setup (42). Enriched CD8 + T cells (10 4 –10 5 ) were mixed with BMDC stimulator cells (5 × 10 4 /well) in RPMI-10 medium and plated in triplicate wells.…”

Section: Methodsmentioning

confidence: 99%

Nonconventional CD8+ T Cell Responses to Listeria Infection in Mice Lacking MHC Class Ia and H2-M3

Cho

Choi

et al. 2011

The Journal of Immunology

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CD8+ T cells restricted to MHC class Ib molecules other than H2-M3 have been shown to recognize bacterial Ags. However, the contribution of these T cells to immune responses against bacterial infection is not well defined. To investigate the immune potential of MHC class Ib-restricted CD8+ T cells, we have generated mice that lack both MHC class Ia and H2-M3 molecules (Kb−/−D b−/−M3−/−). The CD8+ T cells present in Kb−/−D b−/−M3−/− mice display an activated surface phenotype and are able to secrete IFN-γ rapidly upon anti-CD3 and anti-CD28 stimulation. Although the CD8+ T cell population is reduced in Kb−/−D b−/−M3−/− mice compared with that in Kb−/−D b−/− mice, this population retains the capacity to expand significantly in response to primary infection with the bacteria Listeria monocytogenes. However, Kb−/−D b−/−M3−/− CD8+ T cells do not expand upon secondary infection, similar to what has been observed for H2-M3–restricted T cells. CD8+ T cells isolated from Listeria-infected Kb−/−D b−/−M3−/− mice exhibit cytotoxicity and secrete proinflammatory cytokines in response to Listeria-infected APCs. These T cells are protective against primary Listeria infection, as Listeria-infected Kb−/−D b−/−M3−/− mice exhibit reduced bacterial burden compared with that of infected β2-microglobulin–deficient mice that lack MHC class Ib-restricted CD8+ T cells altogether. In addition, adoptive transfer of Listeria-experienced Kb−/−D b−/−M3−/− splenocytes protects recipient mice against subsequent Listeria infection in a CD8+ T cell-dependent manner. These data demonstrate that other MHC class Ib-restricted CD8+ T cells, in addition to H2-M3–restricted T cells, contribute to antilisterial immunity and may contribute to immune responses against other intracellular bacteria.

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“…( 45 ) Cell lines. The derivation and maintenance of the B78H1 transfectants expressing TAP2 (designated H1TAP.11), TAP2 and Q8 (designated H1Q8TAP.11), or TAP2 and Q9 (designated H1Q9TAP.11) have been previously described ( 25 ).…”

Section: Methodsmentioning

confidence: 99%

“…The Qa-2 family is composed of several members, of which Q9 is among the most thoroughly characterized mouse class Ib proteins. Q9 and another Qa-2 family member, Q8, share largely overlapping peptide-binding motifs, despite having > 20 aa diff erences in the ␣ 1 and ␣ 2 domains ( 25 ). To determine whether Q8 and/or Q9 present the VP2.139 epitope to the K b Ϫ / Ϫ D b Ϫ / Ϫ PyV-specifi c CD8 T cell clones, we Chronic encounter by cognate antigen typically directs MHC class Ia -restricted CD8 T cells toward an eff ector differentiation state having curtailed eff ector competency.…”

Section: Visualization Of Q9-vp2139 -Specifi C Cd8 T Cells In Kmentioning

confidence: 99%

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

Swanson

Pack

Hadley

et al. 2008

The Journal of Experimental Medicine

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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.

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The Role of Structurally Conserved Class I MHC in Tumor Rejection: Contribution of the Q8 Locus

Cited by 8 publications

References 47 publications

An MHC Class Ib-Restricted CD8+ T Cell Response to Lymphocytic Choriomeningitis Virus

An MHC Class Ib-Restricted CD8+ T Cell Response to Lymphocytic Choriomeningitis Virus

Nonconventional CD8+ T Cell Responses to Listeria Infection in Mice Lacking MHC Class Ia and H2-M3

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

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