Article ; Online: Different routes of MHC-I delivery to phagosomes and their consequences to CD8 T cell immunity.
2023 Volume 66, Page(s) 101713
Abstract: Dendritic cells (DCs) present internalized antigens to CD8 T cells through cross-presentation by major histocompatibility complex class I (MHC-I) molecules. While conventional cDC1 excel at cross-presentation, cDC2 can be licensed to cross-present during ...
| Abstract | Dendritic cells (DCs) present internalized antigens to CD8 T cells through cross-presentation by major histocompatibility complex class I (MHC-I) molecules. While conventional cDC1 excel at cross-presentation, cDC2 can be licensed to cross-present during infection by signals from inflammatory receptors, most prominently Toll-like receptors (TLRs). At the core of the regulation of cross-presentation by TLRs is the control of subcellular MHC-I traffic. Within DCs, MHC-I are enriched within endosomal recycling compartments (ERC) and traffic to microbe-carrying phagosomes under the control of phagosome-compartmentalized TLR signals to favor CD8 T cell cross-priming to microbial antigens. Viral blockade of the transporter associated with antigen processing (TAP), known to inhibit the classic MHC-I presentation of cytoplasmic protein-derived peptides, depletes the ERC stores of MHC-I to simultaneously also block TLR-regulated cross-presentation. DCs counter this impairment in the two major pathways of MHC-I presentation to CD8 T cells by mobilizing noncanonical cross-presentation, which delivers MHC-I to phagosomes from a new location in the ER-Golgi intermediate compartment (ERGIC) where MHC-I abnormally accumulate upon TAP blockade. Noncanonical cross-presentation thus rescues MHC-I presentation and cross-primes TAP-independent CD8 T cells best-matched against target cells infected with immune evasive viruses. Because noncanonical cross-presentation relies on a phagosome delivery route of MHC-I that is not under TLR control, it risks potential cross-presentation of self-antigens during infection. Here I review these findings to illustrate how the subcellular route of MHC-I to phagosomes critically impacts the regulation of cross-presentation and the nature of the CD8 T cell response to infection and cancer. I highlight important and novel implications to CD8 T cell vaccines and immunotherapy. |
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| MeSH term(s) | Humans ; Dendritic Cells ; Histocompatibility Antigens Class I ; CD8-Positive T-Lymphocytes ; Antigen Presentation ; Phagosomes/metabolism ; Antigens ; Toll-Like Receptors ; HLA Antigens/metabolism |
| Chemical Substances | Histocompatibility Antigens Class I ; Antigens ; Toll-Like Receptors ; HLA Antigens |
| Language | English |
| Publishing date | 2023-01-25 |
| Publishing country | England |
| Document type | Journal Article ; Review ; Research Support, N.I.H., Extramural |
| ZDB-ID | 1018141-6 |
| ISSN | 1096-3618 ; 1044-5323 |
| ISSN (online) | 1096-3618 |
| ISSN | 1044-5323 |
| DOI | 10.1016/j.smim.2023.101713 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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