087 IL-27 signaling is relevant for IL-15 production and T cell cluster maintenance in allergic contact hypersensitivity

Abstract

Allergic contact dermatitis (ACD) results from a T-cell response to hapten/allergens applied to the skin. Following sensitization, specific T-cells are first generated and activated in the lymph node, and some Ag-specific T cells remain in the skin. Re-exposure to the relevant hapten/allergen initiates the efferent phase and clinical expression of ACD, characterized by local T cell activation and recruitment of specific T cells to the sites of allergen challenge. IL-15 is essential for allergic contact hypersensitivity pathogenesis and plays a pivotal role in both T-cell activation, survival and effector functions and, yet, paradoxically, it also provides anti-apoptotic signals in keratinocytes. IL-15 regulation in the skin is not well known. We made the unexpected observation, that in contrast to non-lesional skin of ACD patients, in the skin of 72 hrs patch-tested individuals (effector phase of ACD), IL-15 and anti-apoptotic BCL2 localized to dermal T cell DC clusters and to a much lesser extent to the epidermis. Interestingly, increased BCL2 was expressed in T cells within the clusters and was associated with and directly adjacent to IL-27-producing CD14+ cells in positive patch-tested induced ACD. Monocytic cells, including human DC-like THP1, and murine BMDC up-regulated IL15 mRNA upon IL-27 stimulation. IL-27 was also found to directly stimulate IL15 mRNA in human epidermal keratinocytes in a STAT-1 dependent manner as evidenced by rapid p-STAT1 nuclear translocation and abrogation of this response by silencing STAT1 (p<0.05). We next tested the functional in vivo relevance of IL-27 signaling in a mouse model of hapten/allergen-induced dermal T cell clusters. Administration of IL-27 neutralizing antibody (i.d.) in these mice decreased the number of T cell clusters and resulted in downregulation of BCL2 in T cells supporting a regulatory role of IL-27 on T cell survival possibly via IL-15. Overall, these findings implicate the IL-27 pathway as a potential therapeutic agent in regulating cutaneous T cell immunity.