mRNA vaccines engage unconventional pathways in CD8+ T cell priming
(1) Jo S (2) Li L (3) Thakur C (4) Telfer KA (5) Sultan H (6) Ohara RA (7) He M (8) Nam G (9) Chen J (10) Ou F (11) Draghi M (12) Valiante NM (13) Schreiber RD (14) Randolph GJ (15) Saligrama N (16) Murphy TL (17) Gillanders WE (18) Murphy KM
Jo et al. investigated mechanisms of CD8+ T cell priming induced by mRNA-LNP vaccines. Priming occurred in lymphoid organs, using cDC1s and cDC2s as APCs. Cross-presentation was not a primary mechanism; instead, cross-dressing contributed to cDC2-induced priming, which was dependent on type I IFN signaling. CD8+ T cells primed this way exhibited antitumor activity, and functional memory cells were induced. cDC1 induced more cycling and stem-like populations, while cDC2 induced more clonally expanded terminal effector cells.
(1) Jo S (2) Li L (3) Thakur C (4) Telfer KA (5) Sultan H (6) Ohara RA (7) He M (8) Nam G (9) Chen J (10) Ou F (11) Draghi M (12) Valiante NM (13) Schreiber RD (14) Randolph GJ (15) Saligrama N (16) Murphy TL (17) Gillanders WE (18) Murphy KM
Jo et al. investigated mechanisms of CD8+ T cell priming induced by mRNA-LNP vaccines. Priming occurred in lymphoid organs, using cDC1s and cDC2s as APCs. Cross-presentation was not a primary mechanism; instead, cross-dressing contributed to cDC2-induced priming, which was dependent on type I IFN signaling. CD8+ T cells primed this way exhibited antitumor activity, and functional memory cells were induced. cDC1 induced more cycling and stem-like populations, while cDC2 induced more clonally expanded terminal effector cells.
ABSTRACT: Vaccines composed of mRNA and lipid nanoparticles (LNPs) activate B cells and T cells by inducing in vivo production of specific protein antigens. While B cells can be activated directly by antigens, T cell activation requires antigen processing and presentation by MHC molecules on specialized antigen-presenting cells (APCs). In response to viral infections, tumours, and protein- and cDNA-based vaccines, antigen presentation to CD8(+) T cells is particularly dependent on type 1 conventional dendritic (cDC1) cells, which are specialized for efficient cross-presentation of exogenous antigens(1-4). However, whether similar mechanisms have a role in mRNA-LNP vaccination is unclear. Here we report that mRNA-LNP vaccines do not require cDC1 cells or the WDFY4-dependent cross-presentation pathway for CD8(+) T cell priming but instead engage both cDC1 and cDC2 cells redundantly. While CD8(+) T cells primed exclusively by either cDC1 or cDC2 cells showed phenotypic differences, both could mediate anti-tumour responses and memory formation. Importantly, acquisition by cDCs of peptide-MHC-I complexes from non-haematopoietic cells, called cross-dressing, provides a substantial component of CD8(+) T cell priming, in a manner dependent on type I interferon. mRNA-LNP induction of cross-dressing might explain their ability to activate CD8(+) T cells against antigens not encoded by the vaccine.
Author Info:
(1) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (2) Department of Surgery, Washington University in St Louis Sc
hool of Medicine, St Louis, MO, USA. (3) Department of Neurology, Washington University School of Medicine, St Louis, MO, USA. (4) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (5) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University in St Louis School of Medicine, St Louis, MO, USA. (6) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (7) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (8) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (9) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (10) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (11) Innovac Therapeutics, Cambridge, MA, USA. (12) Innovac Therapeutics, Cambridge, MA, USA. (13) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University in St Louis School of Medicine, St Louis, MO, USA. The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St Louis, MO, USA. (14) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (15) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. Department of Neurology, Washington University School of Medicine, St Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University in St Louis School of Medicine, St Louis, MO, USA. (16) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (17) Department of Surgery, Washington University in St Louis School of Medicine, St Louis, MO, USA. gillandersw@wustl.edu. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University in St Louis School of Medicine, St Louis, MO, USA. gillandersw@wustl.edu. The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St Louis, MO, USA. gillandersw@wustl.edu. (18) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. kmurphy@wustl.edu.
