TLR Signals Induce Phagosomal MHC-I Delivery from the Endosomal Recycling Compartment to Allow Cross-Presentation

Abstract

SUMMARY Adaptation of the endoplasmic reticulum (ER) pathway for MHC class I (MHC-I) presentation in dendritic cells enables cross-presentation of peptides derived from phagocytosed microbes, infected cells, or tumor cells to CD8 T cells. How these peptides intersect with MHC-I molecules remains poorly understood. Here, we show that MHC-I selectively accumulate within phagosomes carrying microbial components, which engage Toll-like receptor (TLR) signaling. Although cross-presentation requires Sec22b-mediated phagosomal recruitment of the peptide loading complex from the ER-Golgi intermediate compartment (ERGIC), this step is independent of TLR signaling and does not deliver MHC-I. Instead, MHC-I are recruited from an endosomal recycling compartment (ERC), which is marked by Rab11a, VAMP3/cellubrevin, and VAMP8/endobrevin and holds large reserves of MHC-I. While Rab11a activity stocks ERC stores with MHC-I, MyD88-dependent TLR signals drive IκB-kinase (IKK)2-mediated phosphorylation of phagosome-associated SNAP23. Phospho-SNAP23 stabilizes SNARE complexes orchestrating ERC-phagosome fusion, enrichment of phagosomes with ERC-derived MHC-I, and subsequent cross-presentation during infection.

T Cell Priming by Activated Nlrc5-Deficient Dendritic Cells Is Unaffected despite Partially Reduced MHC Class I Levels

“…Therefore, NLRC5 is not directly regulating the subcellular distribution of MHCI, which is rather fine-tuned based on the size of the intracellular MHCI pool. As MHC display is known to be strongly regulated also at posttranslational levels, we can postulate that MHCI trafficking and degradation are controlled through compensatory mechanisms influenced by the intracellular MHCI pool (20)(21)(22)(23)(24)(25). Of note, we observed a dramatic loss of intracellular H2-K molecules and a remarkable decrease in surface levels 2 d after Nlrc5 2/2 DC activation.…”

“…We therefore quantified only DC ability to cross-prime T cells, what encompasses both Ag display and costimulatory ability (17)(18)(19)27). We therefore speculate that the unaffected costimulatory capacity and the relative abundance of MHCI molecules at the surface of Nlrc5 2/2 DCs, which can feed into the crosspresentation pathway (23,28), contribute to efficient T cell cross-priming.…”

Cellular and molecular regulation of innate inflammatory responses

“…While Rab11a activity recruits and keeps MHC-I within endosomal recycling compartment (ERC) under steady condition, MyD88-dependent TLR signals drive IKK2-mediated phosphorylation of phagosome-associated SNAP23, orchestrating ERC-phagosome fusion, promoting enrichment of phagosomes with ERC-derived MHC-I, and finally allowing cross-presentation during infection. 139 Transcription factor TFEB, 140 cell stress sensor IRE-1α, [141][142][143] NF-κB-inducing kinase (NIK) 144 and the lectin Siglec-G 145 have been shown to regulate DC cross-presentation in initiating antigen-specific CTL responses via distinct molecular mechanisms. For example, Siglec-G inhibits cross-presentation by CD8α+ DC via impairing the formation of the MHC class I-exogenous antigen peptide complex, contributing to suppression of CTL responses to intracellular bacterial infection with Listeria monocytogenes or Mycobacterium bovis bacillus Calmette-Guérin and tumors.…”

Carbon monoxide impairs mitochondria‐dependent endosomal maturation and antigen presentation in dendritic cells

“…10A, (2) and (3)) and the ATP-dependent dynein endosomal transport [48,[100][101][102][103]. Furthermore, MHC-I transport to ERgosomes requires IKK2 activity [92] whose function seems to be glycolysis-dependent ([104, 105] and Fig. 10A, (9)).…”