Background:Contact hypersensitivity (CHS) is a T cell-mediated cutaneous inflammatory response which includes three phases of priming/sensitization, elicitation, and resolution,mirroring many aspects of allogeneic responses. The detailed mechanisms of immune cell recruitment and migration for each phase are not well characterized, and specific regulators of each phase remain undefined. Lymphatic endothelial cells express the lymphotoxin beta receptor (LTβR) which regulates endothelial function and migration of leukocytes into lymphatic vessels. The LTβR signals through distinct classical and non-classical NFκB pathways for separate homeostatic and inflammatory responses. We hypothesized that inhibitors of the distinct signaling pathways of the LTβR could regulate CHS.

Methods:A decoy receptor peptide that specifically targets the LTβR-NFκB NIK signaling was designed and administered in vitro or in vivo. T cell and dendritic cell (DC) migration were assessed in vivo and in vitro. The CHS response was measured by mouse ear swelling and immunohistochemistry.

Results:Application of a decoy peptide which inhibits non-classical NIK signaling at the hapten sensitization phase ameliorates CHS, with fewer T cells and DC infiltrating the antigen challenged tissues. The decoy peptide inhibits dermal DC migration to the draining LNs, thereby reducing T cell priming. Local treatment with the inhibitory peptide at the time of hapten re-challenge also inhibits CHS by inhibiting DC migration to local lymph nodes and subsequent T cell activation and recruitment to the inflamed tissues. However, local application of the decoy peptide at the resolution stage extended CHS by preventing T cell and DC egress from the inflamed tissues. In contrast, an alternative blocking decoy peptide that inhibits only the classical NFkB pathway of LTβR signaling, accelerates resolution of CHS inflammation at this phase by promoting T cell and DC egress from the inflamed tissues.

Conclusions:LTβR-mediated non-classical NFκB NIK signaling regulates DC migration from dermal tissues to local draining LNs and regulates T cell migration into and out of inflamed tissues. Classical NFκB signaling also regulates leukocyte migration but is mechanistically distinct to that of NIK signaling. The decoy peptides that inhibit the separate pathways of LTβR signaling are novel interventions to regulate immune cell migration during distinct phases of the immune response. Their structures and inhibitory mechanisms may lead to the development of specific therapeutics.

CITATION INFORMATION: Piao W., Xiong Y., Li L., Saxena V., Bromberg J. Targeting Lymphotoxin Signaling in Lymphatics Regulates Immune Sensitization, Elicitation, and Resolution Am J Transplant. 2017;17 (suppl 3).

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