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Tailoring In Vivo Cytotoxicity Assays to Study Immunodominance in Tumor-specific CD8+ T Cell Responses
Published on: May 6, 2019
Dendritic cells can prime anti-tumor CD8+ T cell responses through major histocompatibility complex cross-dressing
Brendan W MacNabb1, Sravya Tumuluru2, Xiufen Chen3
1Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.
Insights
MHC-I cross-dressing, where dendritic cells (DCs) acquire tumor MHC-I molecules, is vital for anti-tumor immunity. This process enhances CD8+ T cell activation and mirrors the cancer cell peptidome for effective immune responses.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Dendritic cells (DCs) initiate anti-tumor CD8+ T cell responses primarily through antigen cross-presentation.
- The role of other antigen presentation pathways in anti-tumor immunity remains incompletely understood.
Purpose of the Study:
- To investigate the significance of MHC-I cross-dressing in anti-tumor immunity.
- To determine if MHC-I cross-dressing contributes to CD8+ T cell activation and priming against tumors.
Main Methods:
- Utilized two subcutaneous tumor models to assess the impact of cancer cell MHC-I expression.
- Investigated in vivo acquisition of tumor-derived peptide:MHC-I complexes by DCs.
- Detected transfer of tumor-derived human leukocyte antigen (HLA) molecules to myeloid cells in vitro and in human tumor xenografts.
Main Results:
- Cancer cell MHC-I expression was essential for optimal CD8+ T cell activation.
- In vivo acquisition of tumor-derived peptide:MHC-I by DCs effectively primed antigen-specific CD8+ T cells.
- Transfer of tumor-derived HLA molecules to myeloid cells was observed.
Conclusions:
- MHC-I cross-dressing is a critical pathway for anti-tumor CD8+ T cell priming by DCs.
- This pathway not only enhances tumor antigen presentation but may also allow DCs to better represent the cancer cell peptidome.
Abstract:
Antigen cross-presentation, wherein dendritic cells (DCs) present exogenous antigen on major histocompatibility class I (MHC-I) molecules, is considered the primary mechanism by which DCs initiate tumor-specific CD8+ T cell responses. Here, we demonstrate that MHC-I cross-dressing, an antigen presentation pathway in which DCs acquire and display intact tumor-derived peptide:MHC-I molecules, is also important in orchestrating anti-tumor immunity. Cancer cell MHC-I expression was required for optimal CD8+ T cell activation in two subcutaneous tumor models. In vivo acquisition of tumor-derived peptide:MHC-I molecules by DCs was sufficient to induce antigen-specific CD8+ T cell priming. Transfer of tumor-derived human leukocyte antigen (HLA) molecules to myeloid cells was detected in vitro and in human tumor xenografts. In conclusion, MHC-I cross-dressing is crucial for anti-tumor CD8+ T cell priming by DCs. In addition to quantitatively enhancing tumor antigen presentation, MHC cross-dressing might also enable DCs to more faithfully and efficiently mirror the cancer cell peptidome.
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