Zabala-Peñafiel, Gonzalez-Lombana et al. showed that mice vaccinated s.c. with LNPs containing mRNA encoding leishmanial PEPCK antigen generated specific dLN and splenic Th1 and T follicular helper cells, but few dermal resident memory T cells (dTrm). These mice did not mount delayed-type hypersensitivity (DTH, which requires dTrm in non-inflamed skin) or protective responses to L. major intradermal infection. Delivering IL-12 mRNA-LNPs with PEPCK vaccines boosted levels of specific Th1 cells with skin-homing (selectin+) and memory markers in LN, increased dTrm cells in inflamed and non-inflamed skin, and induced DTH and protective responses to Leishmania challenge.
Contributed by Paula Hochman
ABSTRACT: Dermal resident memory CD4(+) T cells (dTrm) provide protection against vector-borne infections. However, the factors that promote their development remain unclear. We tested if an mRNA vaccine, encoding a protective leishmanial antigen, induced dTrm cells. The mRNA vaccine induced robust systemic T-cell responses, but few Trm cells were found in the skin. Since IL-12 promotes Th1 responses, we tested whether IL-12 mRNA combined with the mRNA vaccine could enhance dTrm cell development. This combination significantly expanded Leishmania-specific Th1 cells expressing skin-homing molecules and memory T cell markers in the draining lymph node. Additionally, higher numbers of dTrm cells were maintained in the skin, and mice exhibited functional immunity indicated by a delayed hypersensitivity response and protection upon challenge with Leishmania. These findings highlight IL-12 as a key driver of CD4(+) dTrm development, enabling their global seeding across the skin, and underscore the potential of IL-12-enhanced mRNA vaccines to generate durable immunity against cutaneous leishmaniasis and other skin-targeted infections.
Author Info: (1) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (2) Department of Pathobiology, School of Veterinary Medicine, Uni
Author Info: (1) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (2) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (3) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. (4) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (5) Department of Immunology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada. (6) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (7) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (8) Acuitas Therapeutics, Vancouver, BC, Canada. (9) Department of Immunology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada. (10) Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Penn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, PA, USA. (11) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (12) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. pscott@upenn.edu.
