Dendritic cells (DCs) present exogenous antigens via major histocompatibility complex class I (MHC-I) and MHC class II (MHC-II) molecules, activating CD8+ and CD4+ T cells. A critical but poorly understood step in this process is the trafficking of peptide-loaded MHC molecules from the endocytic system to the cell surface. In this study, we demonstrate that the Golgi reassembly-stacking protein of 55 kDa (GRASP55), which has been shown to have no role in stacking, is essential for antigen presentation. Using soluble, bead-coated, and bacterial-bound antigens, we found significantly impaired exogenous antigen presentation in GRASP55-deficient bone-marrow-derived DCs (BMDCs). Notably, GRASP55 was recruited to late phagosomes, and our data suggest that it is crucial for sorting MHC-I and MHC-II molecules, facilitating their trafficking to the plasma membrane. Our findings highlight the vital role of GRASP55 in the intracellular transport of MHC molecules bound to their respective peptides during exogenous antigen presentation.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

CD8+ T cell exhaustion (TEX) impairs the ability of T cells to clear chronic infection or cancer. While TEX are hypofunctional, some TEX retain effector gene signatures, a feature associated with killer lectin-like receptor (KLR) expression. Although KLR+ TEX (TKLR) may improve control of chronic antigen, the signaling molecules regulating this population are poorly understood. Using single-cell RNA sequencing (scRNA-seq), flow cytometry, RNA velocity, and single-cell T cell receptor sequencing (scTCR-seq), we demonstrate that deleting the pseudokinase Trib1 shifts TEX toward CX3CR1+ intermediates with robust enrichment of TKLR via clonal T cell expansion. Adoptive transfer studies demonstrate this shift toward CD8+ TKLR in Trib1-deficient cells is CD8 intrinsic, while CD4-depletion studies demonstrate CD4+ T cells are required for improved viral control in Trib1 conditional knockout mice. Further, Trib1 loss augments anti-programmed death-ligand 1 (PD-L1) blockade to improve viral clearance. These data identify Trib1 as an important regulator of CD8+ TEX whose targeting enhances the TKLR effector state and improves checkpoint inhibitor therapy.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.