AUTHOR=Alcain Julieta , Infante Cruz Alejandra del Pilar , Barrientos Gabriela , Vanzulli Silvia , Salamone Gabriela , Vermeulen Mónica 

TITLE=Mechanisms of unconventional CD8 Tc2 lymphocyte induction in allergic contact dermatitis: Role of H3/H4 histamine receptors

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.999852

DOI=10.3389/fimmu.2022.999852

ISSN=1664-3224

ABSTRACT=<p>Histamine (HA) is a potent mediator that plays a central role in inflammation and allergy, acting through four G-protein-coupled receptors (i.e. H<sub>1</sub>–H<sub>4</sub>). HA is an accepted promoter of type 2 immunity in CD4<sup>+</sup> T cells during hypersensitivity. Previously, we demonstrated that HA can promote antigen cross-presentation, inducing the activation of antigen-specific CD8<sup>+</sup> T cells in an asthmatic murine model. Non-classical CD8+ T-cell profiles, such as Tc2 or Tc17, are associated with allergic disease persistence and chronicity. In this paper, we focus on the role of the H<sub>3</sub> receptor (H<sub>3</sub>R) and the H<sub>4</sub> receptor (H<sub>4</sub>R) in the development of allergic contact dermatitis. We were able to show that induction of the type 2 profiles associated with interleukin 13 production, both by CD4 and CD8 lymphocytes, depend on the interaction of HA with H<sub>3</sub>R and H<sub>4</sub>R. Blocking both receptors using the selective H<sub>3</sub>/H<sub>4</sub> receptor antagonist thioperamide or the selective H<sub>4</sub>R ligand JNJ777120 reduces the inflammatory response, inducing an immunosuppressive profile associated with the increased proportion of FOXp3<sup>+</sup> regulatory T lymphocytes and CD11b<sup>+</sup>Gr-1<sup>+</sup> myeloid suppressor cells. Interestingly, in dendritic cells, only H<sub>4</sub>R blockade, and not H<sub>3</sub>R blockade, is capable of modulating most of the inflammatory effects observed in our model.</p>