Constitutive TGFβ signaling prevents inflammation-induced Langerhans cell migration

Abstract

Abstract Keratinocytes (KCs) that form the epidermis create a unique barrier niche for cells of the immune system such as Langerhans cells (LCs) and CD8+ resident memory T cells (TRM). These leukocytes provide host-defense but also initiate and maintain autoimmune skin diseases. Hence, elucidating the mechanisms by which CD8+ TRM and LC maintain epidermal residency is of great therapeutic interest. Both cell types require active TGFβ1 to maintain their steady-state epidermal retention. In the epidermis, inactive LAP-TGFβ1 is exclusively activated into active TGFβ1 by integrins ανβ6 and ανβ8 expressed by KCs. However, the relationship between TGFβ1 and LC migration in response to inflammatory stimuli remains unknown. To determine whether enforced TGFβ1 signaling can overcome inflammation-induce LC migration, we generated huLangerin-CreERT2x TGFβRI-CALxL mice (TGFβR1-CALC) that allow for tamoxifen-induced ligand-independent TGFβRI signaling. Enforced TGFβRI signaling in LC prevented migration in response to UVB, chemical haptens, C. albicans epicutaneous infection as well as dermal injection of TNFα and IL1β. LC from TGFβR1-CALC mice did not egress from the epidermis or enter the draining lymph nodes. Notably, in WT mice, we did not observe reduced KC expression of integrin ανβ6 or ανβ8 and levels of pSMAD2 in LC did not decrease in inflammatory contexts. Thus, although enforced TGFβRI signaling can overcome inflammation-induced migratory signals, but the loss of TGFβRI signaling is not required for LC migration. These data are consistent with a model in which TGFβRI signaling drives a LC-intrinsic retention program under homeostatic conditions that is overcome or inhibited by inflammatory cues.