Using LNP-encapsulated mRNA vaccines encoding HA or NP flu model CD4+ T cell antigens, Rood et al. showed that murine APCs that directly produced antigen (without uptake from an extracellular source) in vitro or after IM vaccination of mice are the optimal APCs for activating T cells in vitro. By using microRNA to enable cell type-specific mRNA depletion in mRNA-LNP-vaccinated mice, the researchers showed that hematopoietic cells were essential for elicitation of optimal antigen-specific CD4+ T cell, Tfh cell, and Ab responses, with minimal impact of skeletal muscle-derived antigens.
Contributed by Paula Hochman
ABSTRACT: Lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccines elicit robust CD4(+) T cell responses, yet the mechanisms underlying this T cell priming remain unknown. Antigens presented to CD4(+) T cells on major histocompatibility complex class II (MHC II) are traditionally acquired by antigen presenting cells (APCs) from extracellular sources. Here we show that vaccine-specific CD4(+) T cell responses instead rely on antigen directly expressed within APCs, without extracellular transit. Murine APCs treated with mRNA-LNP vaccines activate T cells more efficiently when presenting antigen produced internally, rather than acquired externally. Immunization with mRNA-LNP vaccines engineered to inhibit antigen expression in APCs results in lower antigen-specific CD4(+) T cell, T follicular helper cell, and antibody responses in mice. In contrast, excluding vaccine antigen from muscle cells minimally affects CD4(+) T cell responses. Our findings demonstrate that endogenous antigen presentation is essential to mRNA-LNP vaccine-induced immune responses and refine paradigms of MHC II-restricted antigen processing and presentation.
Author Info: (1) Division of Rheumatology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. ROODJ@chop.edu. (2) School of Engineering and Applied Science, University of Pennsylvania,
Author Info: (1) Division of Rheumatology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. ROODJ@chop.edu. (2) School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (3) Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Bristol Myers Squibb, Lawrenceville, NJ, USA. (4) Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (5) Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA. (6) Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Jefferson College of Life Sciences, Thomas Jefferson University, Philadelphia, PA, USA. (7) Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA. (8) Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Drexel University College of Medicine at Tower Health, Wyomissing, PA, USA. (9) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (10) Genevant Sciences Corporation, Vancouver, British Columbia, Canada. (11) Genevant Sciences Corporation, Vancouver, British Columbia, Canada. (12) Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (13) Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (14) Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, USA. (15) Genevant Sciences Corporation, Vancouver, British Columbia, Canada. (16) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (17) Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA. eisenlc@pennmedicine.upenn.edu. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. eisenlc@pennmedicine.upenn.edu.
