Mechanisms of unconventional CD8 Tc2 lymphocyte induction in allergic contact dermatitis: Role of H 3 /H 4 histamine receptors.

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 ₁ -H ₄ ). 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 H ₃ receptor (H ₃ R) and the H ₄ receptor (H ₄ 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 ₃ R and H ₄ R. Blocking both receptors using the selective H ₃ /H ₄ receptor antagonist thioperamide or the selective H ₄ R 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 H ₄ R blockade, and not H ₃ R blockade, is capable of modulating most of the inflammatory effects observed in our model.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2022 Alcain, Infante Cruz, Barrientos, Vanzulli, Salamone and Vermeulen.)