Recipient Langerhans Cells Are Neither Required Nor Sufficient for GVHD Induction in MHC-Matched Allogeneic BMT, but a Langerin+ Cell Is a Pivotal Regulator of Langerhans Cell Turnover Post Transplantation
Authors: Li Hongmei , Kaplan Daniel , Demetris Anthony Jake , McNiff Jennifer , Shlomchik Mark , Shlomchik Warren D. 
Published: October 2019

Graft-versus-host disease (GVHD) is initiated when alloreactive donor T cells are primed by professional antigen-presenting cells (APCs) to undergo clonal expansion and maturation. Host APCs that survive pretransplant conditioning play an essential role in this T cell activation, and are an attractive target for GVHD prevention and treatment. However, APCs are diverse in phenotype, location and function and an understanding of the roles of distinct subsets is an important first step in developing APC-targeted therapies. Skin is the most frequently affected organ in GVHD. Langerhans cells (LCs), characterized by expression of Langerin, are a major APC in the epidermis, and thus it was logical to hypothesize that host LCs would have a role in GVHD induction. Indeed, in an MHC-mismatched model, Merad et al. showed that host LCs persist after T cell-depleted (TCD) but not T cell-replete bone marrow transplant (BMT), and that these host LCs in donor→host chimeras are sufficient to induce skin GVHD after a second allogeneic bone marrow transplant (alloBMT). However, this work did not examine the role of recipient LCs when all other APCs are intact, the scenario at the time of transplant in all patients. To address this question, we created a transgenic mouse that constitutively lacks epidermal LCs. We did so by expressing diphtheria toxin A chain (DTA) driven by the human Langerin gene (Kaplan, et al 2005) in a bacterial artificial chromosome (BAC). We used Langerin-DTA BAC transgene positive (Tg+) mice or Tg-littermates as recipients in the C3H.SW (H-2b)→B6 (H-2b) strain paring, in which recipient APCs are necessary and sufficient for GVHD induction. Tg+ and Tg− CD8 recipients developed similar GVHD as measured by weight loss and clinical skin disease. Tg+ and Tg− CD8 recipients also had comparable pathologic GVHD of the skin, ear, liver and colon. To generalize these findings, we used B6bm12 →B6 strain pairing, an MHCII-mismatched CD4-dependent GVHD model, in which recipient APCs are also required (Teshima et al, 2002). Tg+ and Tg− CD4 recipients developed similar weight loss and pathologic changes in the tongue and liver, primary sites of GVHD in this model. Thus, in both MHC-matched and MHC-mismatched models in which recipient APCs are absolutely required, the specific absence of recipient epidermal LCs did not affect clinical or histological GVHD. We also analyzed LC turnover in these alloBMT recipients. As previously reported, LCs remained host-derived in B6 Tg− recipients of TCD C3H.SW bone marrow. Given our prior result that C3H.SW → B6 chimeras are resistant to GVHD induction by a second alloBMT from C3H. SW donors (Shlomchik, et al 1999), unlike in the MHC-mismatched model employed by Merad, residual host LCs are insufficient to initiate GVHD in this MHC-matched system. In B6 Tg− recipients of TCD C3H.SW bone marrow plus GVHD-inducing CD8 cells, LC turnover varied by mouse and ranged from all host or donor to a mix of donor and host LCs. This variability could relate to the extent of skin GVHD, as we previously found that epidermal MHCII+ cells in skin GVHD lesions in this model are donor-derived (Matte et all, 2004). Strikingly, in contrast to Tg− recipients, donor-derived LCs developed in Tg+ recipients of TCD C3H.SW bone marrow. Donor LCs also engrafted in Tg+ recipients of TCD bone marrow from Tg− but otherwise syngeneic littermates or B6 RAG1−/− T cell-deficient donors. Thus, in contrast to LC-replete mice, neither allogeneic donor T cells nor UV-induced inflammation was required for donor LC engraftment in LC-deficient hosts. These data indicate that a Langerin+ cell, absent in Langerin-DTA Tg+ mice, regulates LC turnover in the absence of inflammation. Work is underway to identify this key cell.