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

Abstract

Histamine (HA) is a potent mediator that plays a central role in inflammation and allergy, acting through four G-protein-coupled receptors (i.e. H₁-H₄). HA is an accepted promoter of type 2 immunity in CD4⁺ T cells during hypersensitivity. Previously, we demonstrated that HA can promote antigen cross-presentation, inducing the activation of antigen-specific CD8⁺ 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 H₃ receptor (H₃R) and the H₄ receptor (H₄R) 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 H₃R and H₄R. Blocking both receptors using the selective H₃/H₄ receptor antagonist thioperamide or the selective H₄R ligand JNJ777120 reduces the inflammatory response, inducing an immunosuppressive profile associated with the increased proportion of FOXp3⁺ regulatory T lymphocytes and CD11b⁺Gr-1⁺ myeloid suppressor cells. Interestingly, in dendritic cells, only H₄R blockade, and not H₃R blockade, is capable of modulating most of the inflammatory effects observed in our model.

Keywords: H4/H3 histamine receptors; allergy contact dermatitis; dendritic cells; immunoregulation; non-conventional CD8+ lymphocytes.