Specialized proteasome subunits have an essential role in the thymic selection of CD8+ T cells

Kincaid, Eleanor Z.; Murata, Shigeo; Tanaka, Keiji; Rock, Kenneth L.

doi:10.1038/ni.3480

Cited by 50 publications

(54 citation statements)

References 48 publications

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“…For the first point, the alternative ligand model of thymic selection may provide the explanation. According to this model, DP cells positively selected in the cortex by peptides specifically expressed there can survive in the medulla because they do not encounter the same peptide; thus, the agonist peptide can induce positive selection in the cortex (36,37). It may be that our culture system reproduces such a cortical, positively selecting microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Regeneration of CD8αβ T Cells from T-cell–Derived iPSC Imparts Potent Tumor Antigen-Specific Cytotoxicity

et al. 2016

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Although adoptive transfer of cytotoxic T lymphocytes (CTL) offer a promising cancer therapeutic direction, the generation of antigen-specific CTL from patients has faced difficulty in efficient expansion in ex vivo culture. To resolve this issue, several groups have proposed that induced pluripotent stem cell technology be applied for the expansion of antigen-specific CTL, which retain expression of the same T-cell receptor as original CTL. However, in these previous studies, the regenerated CTL are mostly of the CD8aa þ innate type and have less antigen-specific cytotoxic activity than primary CTL. Here we report that, by stimulating purified iPSC-derived CD4/CD8 double-positive cells with anti-CD3 antibody, T cells expressing CD8ab were generated and exhibited improved antigen-specific cytotoxicity compared with CD8aa þ CTL. Failure of CD8ab T-cell production using the previous method was found to be due to killing of doublepositive cells by the double-negative cells in the mixed cultures. We found that WT1 tumor antigen-specific CTL regenerated by this method prolonged the survival of mice bearing WT1-expressing leukemic cells. Implementation of our methods may offer a useful clinical tool. Cancer Res; 76(23); 6839-50. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Regeneration of CD8αβ T Cells from T-cell–Derived iPSC Imparts Potent Tumor Antigen-Specific Cytotoxicity

et al. 2016

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“…Since immunoproteasome subunits are also expressed in thymic cells they might influence positive and negative selection processes by producing an altered MHC‐I peptidome. Indeed, several studies have demonstrated that immunoproteasomes determine the CTL repertoire . Osterloh et al.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Kincaid et al. crossed mice lacking all three immunoproteasome subunits with mice lacking the thymosubunit β5t to generate mice lacking all four specialized proteasome β‐subunits (4KO mice) . These mice, expressing only constitutive subunits in all cells, had a profound defect in the generation of CD8 + T cells.…”

Section: Discussionmentioning

confidence: 99%

The immunoproteasome subunit LMP7 is required in the murine thymus for filling up a hole in the T cell repertoire

2017

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Cells of hematopoietic origin express high levels of the immunoproteasome, a cytokine-inducible variant of the proteasome which has been implicated in regulating inflammatory responses and antigen presentation. In the thymus, medullary thymic epithelial cells (mTECs) and cortical thymic epithelial cells (cTECs) do express different proteasome subunits exerting chymotrypsin-like activities suggesting distinct functions in thymic T cell selection. Employing the lymphocytic choriomeningitis virus (LCMV) infection model, we could show that the immunoproteasome subunit LMP7 was absolutely required for the generation of LCMV GP -specific T cells although the class I mediated presentation of GP was not dependent on LMP7. Using bone marrow chimeras and adoptive transfer of LMP7-deficient CD8 T cells into RAG1-deficient mice we show that LMP7-deficient mice lacked GP -specific T cell precursors and that LMP7 was required in radioresistant cells - most likely thymic epithelial cells - to enable their selection. Since LMP7 is strongly expressed in negatively selecting mTECs but barely in positively selecting cTECs our data suggest that LMP7 was required to avoid excessive negative selection of GP -specific T cell precursors. Taken together, this study demonstrates that the immunoproteasome is a crucial factor for filling up holes within the cytotoxic T cell repertoire.

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“…When these subunits are expressed, they preferentially incorporate into newly assembling particles to form immunoproteasomes, that generate a distinct set of peptides during protein degradation[49]. This shift from constitutive to immunoproteasome in cells often enhances the generation of peptides presented by MHC I molecules, including many unique ones[50]. Generation of new peptides will be at the cost of other peptide fragments that are cleaved to make the new fragment [51].…”

Section: How To Present Your Inner Self? Mhc Class I Moleculesmentioning

confidence: 99%

“…Another set of alternate active site subunits (β1i, β2i, β5t) are expressed uniquely only in cortical thymic epithelial cells (cTECs), where they incorporate into thymoproteasome particles[52]. Among the peptides generated by thymoproteasomes, a number are unique and these play a critical role in the auditioning of developing CD8+ T cells during positive selection and also in allowing many of these cells to avoid subsequent negative selection [50]. Proteasomes but also the cytosolic and ER associated peptidases are variable in content and numbers.…”

Section: How To Present Your Inner Self? Mhc Class I Moleculesmentioning

confidence: 99%

Present Yourself! By MHC Class I and MHC Class II Molecules

Rock

Reits

Neefjes

2016

Trends in Immunology

591

485

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Since the discovery of major histocompatibility complex (MHC) molecules, it took some 40 years to arrive at a coherent picture of how MHC class I and MHC class II molecules really work. This is a story of proteases and MHC-like chaperones that support the MHC class I and II molecules in presenting peptides to the immune system. We now understand that the MHC system shapes both the repertoire of presented peptides and the subsequent T cell responses, with important implications ranging from transplant rejection to tumor immunotherapies. Here we present an illustrated review on the ins and outs of MHC class I and MHC class II antigen presentation.

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Specialized proteasome subunits have an essential role in the thymic selection of CD8+ T cells

Cited by 50 publications

References 48 publications

Regeneration of CD8αβ T Cells from T-cell–Derived iPSC Imparts Potent Tumor Antigen-Specific Cytotoxicity

Regeneration of CD8αβ T Cells from T-cell–Derived iPSC Imparts Potent Tumor Antigen-Specific Cytotoxicity

The immunoproteasome subunit LMP7 is required in the murine thymus for filling up a hole in the T cell repertoire

Present Yourself! By MHC Class I and MHC Class II Molecules

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