Mechanisms of antigen cross-presentation by MHC class I molecules
MHC I 类分子的抗原交叉呈递机制
基本信息
- 批准号:10624950
- 负责人:
- 金额:$ 41.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAntigensAutophagocytosisBindingBiologicalBiotinylationCD8-Positive T-LymphocytesCD8B1 geneCRISPR libraryCandidate Disease GeneCathepsinsCell surfaceCellsComplexCross PresentationCytosolDataDendritic CellsDevelopmentEffector CellEndocytosisEndosomesEnzymesEquilibriumExtravasationGenesHistocompatibility Antigens Class IIn SituIntegral Membrane ProteinLabelLaboratoriesLiteratureMediatingMembraneMinorMolecularPathway interactionsPeptide HydrolasesPeptidesPhagocytosisPhagosomesPhenotypeProcessProtein BiosynthesisProteinsProteomicsRecyclingRepair ComplexRoleRouteT cell responseT-LymphocyteTestingViral ProteinsViruscytotoxiccytotoxic CD8 T cellsdimerdiscountendosome membraneexperimental studylipid transfer proteinmulticatalytic endopeptidase complexpeptide Irecruitrepairedscreeningsmall hairpin RNA
项目摘要
Project Summary
Virus infected cells express MHC-I molecules associated with virus-derived peptides that
are recognized by cytotoxic CD8+ T cells. The peptides are generated by proteasomal
degradation of viral proteins synthesized in the cytosol and bind to assembling MHC-I heavy
chain-β2microglobulin dimers in the ER. Naïve CD8+ T-cells, however, must be primed to induce
a mature cytotoxic phenotype. Priming is generally mediated by DCs that acquire antigens by
endocytosis and/or phagocytosis to generate the MHC-I-bound peptides, a process called
cross-presentation. The mechanisms of cross-presentation remain poorly understood, with only
a few effectors identified and none are absolutely required. We propose that the reason is that
there is not a single cross-presentation pathway. Literature data points to three pathways. In the
first, phagolysosomal proteases (cathepsins) degrade antigens to generate the peptides in situ
and these bind to recycling MHC-I by peptide exchange. We discount this as a major
mechanism because it would result in a mismatch between the MHC-I-peptide complexes
generated by cross-presentation and those generated by proteasomes in the ultimate cytotoxic
CD8+ T cell target, the virus infected cell. In the second, phagocytosed or endocytosed antigens
are transferred across phagosomal/endosomal membranes into the cytosol where, like the
newly synthesized proteins in virus infected cells, they are degraded by cytosolic proteasomes
to generate peptides. These are translocated into the ER (or phagosomes that have recruited
ER components) by the Transporter associated with Antigenic Processing (TAP) and bind to
assembling MHC-I molecules, which are then transported to the cell surface. We propose to
determine the mechanism(s) of translocation from endocytic compartments to the cytosol. In the
third pathway, rather than internalized antigens entering the cytosol, cytosolic proteasomes are
delivered into the lumen of phagosomes and/or endosomes. The antigens are then processed in
situ by the proteasomes to generate peptides that bind to recycling MHC-I. This pathway is
independent of TAP transport of the antigenic peptides but is dependent on proteasome activity.
We propose that the second and third routes of cross-presentation can both operate, the
common denominator being the endpoint, namely antigen recognition by the CD8+ T cells. The
precise mechanisms required to mount and maintain a successful CD8+ T cell response will be
determined.
项目总结
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cutting Edge: Phagosome-associated Autophagosomes Containing Antigens and Proteasomes Drive TAP-Independent Cross-Presentation.
最前沿:含有抗原和蛋白酶体的吞噬体相关自噬体驱动不依赖于 TAP 的交叉呈递。
- DOI:10.4049/jimmunol.2200446
- 发表时间:2024
- 期刊:
- 影响因子:0
- 作者:Sengupta,Debrup;Galicia-Pereyra,Rodrigo;Han,Patrick;Graham,Morven;Liu,Xinran;Arshad,Najla;Cresswell,Peter
- 通讯作者:Cresswell,Peter
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PETER CRESSWELL其他文献
PETER CRESSWELL的其他文献
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{{ truncateString('PETER CRESSWELL', 18)}}的其他基金
SARS-CoV-2 infection and MHC class I function in bats
蝙蝠中的 SARS-CoV-2 感染和 MHC I 类功能
- 批准号:
10549369 - 财政年份:2022
- 资助金额:
$ 41.88万 - 项目类别:
SARS-CoV-2 infection and MHC class I function in bats
蝙蝠中的 SARS-CoV-2 感染和 MHC I 类功能
- 批准号:
10451136 - 财政年份:2022
- 资助金额:
$ 41.88万 - 项目类别:
Mechanisms of antigen cross-presentation by MHC class I molecules
MHC I 类分子的抗原交叉呈递机制
- 批准号:
10413224 - 财政年份:2021
- 资助金额:
$ 41.88万 - 项目类别:
Mechanisms of antigen cross-presentation by MHC class I molecules
MHC I 类分子的抗原交叉呈递机制
- 批准号:
10276760 - 财政年份:2021
- 资助金额:
$ 41.88万 - 项目类别:
The role of GILT in the generation of reactive oxygen species
GILT 在活性氧生成中的作用
- 批准号:
9091406 - 财政年份:2015
- 资助金额:
$ 41.88万 - 项目类别:
The role of GILT in the generation of reactive oxygen species
GILT 在活性氧生成中的作用
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8951439 - 财政年份:2015
- 资助金额:
$ 41.88万 - 项目类别:
Quality Control of MHC Class I Restricted Antigen Processing
MHC I 类限制性抗原加工的质量控制
- 批准号:
8662182 - 财政年份:2012
- 资助金额:
$ 41.88万 - 项目类别:
Quality Control of MHC Class I Restricted Antigen Processing
MHC I 类限制性抗原加工的质量控制
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9925726 - 财政年份:2012
- 资助金额:
$ 41.88万 - 项目类别:
Quality Control of MHC Class I Restricted Antigen Processing
MHC I 类限制性抗原加工的质量控制
- 批准号:
9175668 - 财政年份:2012
- 资助金额:
$ 41.88万 - 项目类别:
Quality Control of MHC Class I Restricted Antigen Processing
MHC I 类限制性抗原加工的质量控制
- 批准号:
9275343 - 财政年份:2012
- 资助金额:
$ 41.88万 - 项目类别:
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