| Langerhans cells (LCs) are specialized hematopoietic cells of the myeloid lineage that represent the sole antigen-presenting cell (APC) of the epidermis in both mouse and man. As a subset of dendritic cells (DCs), LCs are critical mediators of both cutaneous tolerance and adaptive immunity. The work comprising this manuscript specifically focuses on two of the more enigmatic properties of LCs: their involvement in the putative myeloid neoplasia Langerhans Cell Histiocytosis (LCH) and the ability of LCs to withstand lethal doses of ionizing radiation (IR).;LCH is a clonal disorder with elusive etiology, characterized by the accumulation of langerin+ DCs in inflammatory lesions. Recent reports of recurrent BRAF- V600E mutations in lesions LCH patients led us to investigate the role of this protein in its pathogenesis. Vitally, we demonstrate that the pathologic "LCs" of LCH stem from BM-derived DC progenitors. Moreover, the presence of the BRAFV600E allele in LCH patients and a novel mouse model correlates significantly to high-risk disease, whereas restricted expression in LCH lesions correlated to low-risk disease. These data therefore strongly suggest that LCH is, in fact, a myeloid neoplasia of the DC lineage in which disease severity may be directly linked to the presence of a somatic mutation of BRAFV600E in early vs. mature DC precursors.;In this dissertation we also sought to understand the properties of LCs that confer their remarkable resistance to depletion following IR. We discovered that LCs express a pro-survival gene repertoire in response to IR treatment. Accordingly, we show that LCs resist apoptosis following IR and uniquely fail to accumulate DNA damage. Moreover, the cell cycle regulator p21 is solely expressed in LCs at rest, suggesting a novel role of p21 in LC IR-resistance. We subsequently proceed by using antigen targeting to LCs to show that IR induces LC mediated Treg expansion and that this effect is mitigated in p21KO chimeric mice. Furthermore, adoptive transfer of melanoma shows that IR-sensitive LCs drive less Treg expansion and correlate with significantly smaller B16 tumor sizes. Moving forward, these data suggest a novel rationale for the use of adjunct radiotherapy in the treatment of cutaneous tumors. |
