iNKT cells represent a lipid-responsive arm

of the innate immune system that has been implicated in the regulation or promotion of a variety of immune, infectious and neoplastic processes. Invariant natural killer T cells are partially activated at baseline, with stores of both Th1 and Th2 cytokines (e.g. IFN-γ and IL-4, respectively) that can be rapidly secreted [3, 4]. Consistent with this wide-ranging capacity, iNKT cells have been implicated in playing beneficial pro-inflammatory roles (e.g. cancer immunity), deleterious pro-inflammatory roles (e.g. atherosclerosis) and anti-inflammatory roles [e.g. non-alcoholic fatty liver disease (NAFLD), see more graft-versus-host disease (GVHD)] [3, 5, 6]. We have studied iNKT cells in contact sensitivity (CS), also known as contact hypersensitivity or allergic contact dermatitis. CS is a local immune inflammatory response in the skin that occurs following topical exposure to a chemically reactive hapten allergen that covalently binds to self-peptides [7]. Sensitization typically occurs with first exposure to a concentrated dose of hapten,

while elicitation of a profound local inflammatory response may be provoked with subsequent exposure (i.e. challenge) to the same hapten at a much lower dose than required for sensitization. Poison ivy and nickel sensitivity are clinical examples. We have previously described hepatic iNKT cells to be amongst the earliest immune responders following sensitization. As early as 7 min after sensitization, hepatic iNKT cells release IL-4 that binds to Selleckchem Regorafenib IL-4R on peritoneal B-1 B cells, which concurrently receive a second signal via surface B cell receptors of hapten conjugated to circulating self-peptides [8–10]. B-1 B cells are stimulated via Stat-6 signalling to migrate from the peritoneal cavity to the spleen within 24 h to produce antigen-specific IgM antibodies [8, 11]. Meanwhile, naïve T cells are primed via exposure to hapten conjugated to self-peptide that is presented on MHC complexes

by antigen-presenting cells (APC) in the draining lymph nodes of the sensitization site. Upon subsequent exposure, B-1 B cell-generated IgM antibodies bind allergen and then activate complement, triggering mast cells and platelets to locally release Megestrol Acetate vasoactive mediators (serotonin and TNF-α), thereby ultimately enabling local recruitment of primed T cells into the tissues [12–23]. It is an open question of how iNKT cells respond so rapidly to sensitization. The rapidity may be explained by the finding that at baseline, iNKT cells are already partially activated, constitutively expressing IL-4 and IFN-γ [4], likely the result of prior TCR interactions with complexes of self-glycolipids bound within CD1d molecules of APCs. Whether the hepatic lipids that stimulate iNKT cells change in character following sensitization is unknown.