{beta}-Glucosylceramides and Tocopherols Regulate Development and Function of Dendritic Cells [ALLERGY AND OTHER HYPERSENSITIVITIES]

Key Points

β-Glucosylceramides increased development of CD11b+CD11c+ dendritic cells via PKC.

Tocopherol isoforms modified this development of dendritic cells.

DC function was not altered, but increased DC numbers elevated T cell activation.

Visual AbstractFigureFigureAbstract

In humans and mice, offspring of allergic mothers are predisposed to development of allergy. In mice, allergic mothers have elevated β-glucosylceramides (βGlcCers) that are transported to the fetus via the placenta and to offspring via milk. The elevated βGlcCers increase the number of fetal liver CD11c+CD11b+ dendritic cells (DCs) and offspring allergen-induced lung eosinophilia. These effects are modifiable by maternal dietary supplementation with the plant-derived lipids α-tocopherol and γ-tocopherol. It is not known whether βGlcCers and tocopherols directly regulate development of DCs. In this study, we demonstrated that βGlcCers increased development of GM-CSF–stimulated mouse bone marrow–derived DCs (BMDCs) in vitro without altering expression of costimulatory molecules. This increase in BMDC numbers was blocked by α-tocopherol and potentiated by γ-tocopherol. Furthermore, βGlcCers increased protein kinase Cα (PKCα) and PKCδ activation in BMDCs that was blocked by α-tocopherol. In contrast, γ-tocopherol increased BMDC PKCα and PKCδ activation and enhanced the βGlcCer-induced increase in PKCδ activation in a DC subset. Ag processing per DC was minimally enhanced in βGlcCer-treated BMDCs and not altered ex vivo in lung DCs from pups of allergic mothers. Pups of allergic mothers had an increased proportion of CD11b+CD11c+ subsets of DCs, contributing to enhanced stimulation of T cell proliferation ex vivo. Thus, βGlcCer, which is both necessary and sufficient for development of allergic predisposition in offspring of allergic mothers, directly increased development and PKC activation in BMDCs. Furthermore, this was modifiable by dietary tocopherols. This may inform design of future studies for the prevention or intervention in asthma and allergic disease.

Footnotes

This work was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) Grants U01 AI131337 and R01 AI127695 (to J.M.C.-M.), Marshall Klaus Perinatal Research Award (to J.D.L.), and the Pediatric Scientist Development Program (J.D.L.). Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the NIH (Award K12HD000850).

J.D.L., N.A., A.T., and K.T. performed experiments of dendritic cell differentiation and function, participated in figure and manuscript preparation, and did statistical analyses. J.M.C.-M. conceived of the study design and participated in performing experiments, statistical analyses, interpretations, and manuscript preparation.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Abbreviations used in this article:

alvDCalveolar-like dendritic cellBALbronchoalveolar lavageBMDCbone marrow–derived dendritic cellDCdendritic cellβGlcCerβ-glucosylceramidegMFIgeometric mean fluorescence intensityHDMhouse dust mitemDCmonocyte-derived dendritic cellMHCIIMHC class IIPFAparaformaldehydePKCprotein kinase CrDCresident-phenotype dendritic cellαTα-tocopherolγTγ-tocopherolReceived December 20, 2021.Accepted September 7, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.

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