Mitogenic Activities in Neurofibromatosis

Abstract. We study neurofibromas, benign peripheral nerve tumors characteristic of patients with the common dominantly inherited disease neurofibromatosis type 1 (NF1). In the 30-year history of this project we have developed cell and animal models and studied many of the cell types that are recruited to neurofibromas: neurofibroma cells include Schwann cells (SC), which we now know are outnumbered by a combination of fibroblasts, macrophages, and other immune cells. We use a neurofibroma mouse model in which, in the peripheral nervous system, biallelic Nf1 mutations are present only in Schwann cell precursors (SCP) and Schwann cells; other wild type stromal and immune cells are recruited to neurofibromas as they form. We showed that neurofibroma SC and SCP express CXCL10, whose receptor, CXCR3, is expressed on immune cells-- T cells and dendritic cells (DC)-- and that CXCR3 is required for neurofibroma formation. Further, we observed a strong interferon signature in SC and neurofibroma macrophages; interferons are known to stimulate the production of CXCL10 and of CXCL9, chemokines that signal through CXCR3. Our striking Preliminary Data show that neurofibromas require T cells to form, that transfer of T cells back to mice lacking them is sufficient to promote neurofibromas. Mice deficient in a key type of APC, dendritic cells (DCs), also show reduced neurofibroma numbers. Finally, immune cells are known to secrete factors that influence appear to promote Nf1-/- SCP self-renewal and neurofibroma formation. Based on these observations we propose that: (i) Schwann cells/SCP require type I IFN signaling to produce CXCL10 to recruit DCs and T cells. (ii) subset(s) of DCs stimulate tumor-specific T cells to produce IFN-g, which induces Cxcl9 expression by macrophages. (iii) Cxcl9/10 act redundantly to sustain T cell recruitment; and (iv) cytokines produced by immune cells themselves promote SC de-differentiation and neurofibroma development, in a feed-forward loop.