Langerhans cells and lymphatic regulation in immunity - In systemic lupus erythematosus (SLE), skin pathophysiology is linked to autoimmunity. Patients are photosensitive, able to develop inflammatory skin lesions with even ambient ultraviolet radiation (UVR) exposure, which can also induce systemic disease flares. Our long-term goal is to understand mechanisms that link cutaneous photosensitivity with systemic autoimmunity, focusing on skin regulation and the consequences on draining lymph node function. Dermal lymphatic vessels serve to remove interstitial fluid from skin and regulate downstream lymph nodes, the latter by transporting antigens and cells and by directly regulating migrating immune cells. We recently showed that compromised lymphatic flow contributes to increased skin inflammation and lymph node B cell responses in lupus. This proposal investigates mechanisms that regulate lymphatic function to better understand the basis of the dysfunction in disease. Preliminary data show that Langerin-DTA (Lang-DTA) mice constitutively lacking Langerhans cells (LCs) have reduced dermal lymphatic endothelial cell (LEC) numbers, altered LEC phenotype, and poor lymphatic flow, reflecting LEC apoptosis and failure to develop postnatally from 3 weeks of age on. In adulthood, LCs are required to maintain dermal LEC numbers during ultraviolet radiation-induced inflammation. The postnatal lymphatic expansion depends on both vascular endothelial growth factor-C (VEGF-C) and placental growth factor (PGF). Keratinocytes are major VEGF-C expressors in skin and LCs bind VEGF-C in a manner that is reduced with anti-Langerin or with myeloid loss of heparan sulfate 2-O-sulfotransferase 1 (HS2ST1). We further show that restoring postnatal lymphatic expansion with VEGF-C+PGF reduces the known increased T cell priming in response to a contact sensitizer in Lang-DTA mice. The increased T cell priming is associated with reduced LEC IDO1 expression and increased maturation of skin-derived migratory dendritic cells, suggesting that dysregulation of the LC-LEC axis compromises the immune regulatory function of LECs. Together, the data lead to a model of an LC-LEC axis whereby LCs are “licensed” to regulate postnatal LEC development that functions to regulate immunity in adulthood, and this axis is recapitulated during inflammation in adulthood. We hypothesize that LCs are licensed for lymphatic regulation by keratinocyte provision of VEGF-C and LC Langerin and HS2ST1, presumably to bind and transport VEGF-C to the dermal lymphatics, that this LC-mediated regulation shapes tolerogenic programs in LECs, and that a dysfunctional LC-LEC axis contributes to lymphatic dysfunction in SLE. The aims are to 1) delineate the determinants of LC licensing for lymphatic regulation, 2) identify the tolerogenic programs in LECs that are regulated by LCs, and 3) understand the extent to which lymphatic dysfunction in SLE models is related to a dysfunctional LC-LEC axis. This study will help us understand how skin function modulates immunity across time and in disease.
