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.