Different routes of MHC-I delivery to phagosomes and their consequences to CD8 T cell immunity. (March 2023)

• Record Type: Journal Article
• Authors: Blander, J. Magarian
• Is Part Of: Seminars in immunology. Volume 66(2023)
• Publication Date: 2023-03
• Subjects: MHC-I major histocompatibility complex class I -- TAP transporter associated with antigen processing -- DCs dendritic cells -- APCs antigen-presenting cells -- BMDCs bone marrow-derived dendritic cells -- ER endoplasmic reticulum -- ERGIC ER-Golgi intermediate compartment -- ERC endosomal recycling compartment -- DLL1 Delta-like -- ICP47 Infected Cell Protein 47 -- HSV herpes simplex virus -- HCMV human cytomegalovirus -- LN lymph node -- TLR Toll-like receptor -- IKK2 inhibitor of nuclear factor-κB kinase 2 -- SNAP-23 synaptosomal associated protein-23 -- VAMP vesicle-associated membrane protein; Dendritic cells -- Cross-presentation -- Toll-like receptors -- Phagosomes -- Vesicular traffic -- Noncanonical cross-presentation -- CD8 T cells; Immunology -- Periodicals; Allergy and Immunology -- Periodicals; Immunity -- Periodicals; Immunologie -- Périodiques; Electronic journals; 616.079
• DOI: 10.1016/j.smim.2023.101713
• Languages: English
• ISSNs: 1044-5323

Abstract

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. Highlights: Control of MHC-I traffic is at the heart of TLR regulation of cross-presentation. ERC-to-phagosome MHC-I delivery is critical for phagocytic antigen cross-presentation. TAP blockade inhibits classic MHC-presentation and TLR-regulated cross-presentation. ERGIC-to-phagosome MHC-I delivery upon TAP blockade rescues MHC-I presentation. DC-intrinsic noncanonical cross-presentation cross-primes TAP-independent CD8 T cells.