Dendritic cells (DCs) are highly specialized antigen presenting cells found in all lymphoid and non-lymphoid tissues. In the traditional view, DCs are terminally differentiated cells constantly replaced by a pool of circulating precursors. In contrast to this view, we recently demonstrated that in mice, epidermal DCs also called Langerhans cells (LCs) are maintained by local radio-resistant proliferative precursors, throughout life in quiescent skin, and are replaced by circulating precursors only during injuries. We have also discovered that host radio-resistant LCs can persist in recipient mice after allogeneic bone marrow transplant (allo-BMT). Graft versus host disease (GVHD) is a major cause of mortality and morbidity after allo-BMT. Importantly, we found that persistence of host LCs after allo-BMT correlates with severe skin GVHD, while replacement of host LCs by donor LCs improves skin GVHD outcome. Therefore, exploring DC homeostasis in a tissue target of GVHD may help develop new strategies for the treatment of this devastating disease. In addition to LCs, we recently discovered that a subset of DCs in the gut can resist lethal doses of radiation, raising the possibility that LCs may not be unique in being radio-resistant;other tissues may harbor radio- resistant populations that contribute to GVHD. Thus, in aim 1, we will examine the turnover of DCs in the gut, a tissue that is particularly affected by GVHD. Gut DCs constantly transport commensal bacteria and pathogens from the luminal intestine to local lymphoid tissues, playing a critical role in innate and adaptive immunity. To face their continuous migration, gut DCs must be replaced with new cells, but the nature of the committed precursor that maintains the gut DC pool remains elusive. Using novel strategies, we have recently characterized the circulating LC precursor as being a specific subset of circulating monocytes. We also established the sequence of events that leads a monocyte to become a LC and discovered that signaling through the receptor for CSF-1 is required for this process (Nature Immunology in press). Therefore in aim 2, we propose to use similar approaches to explore DC homeostasis in the gut in the steady state and identify the circulating precursor that gives rise to intestinal DCs. Finally, our finding that induction of DC chimerism is critical to prevent GVHD leads us, in aim 3, to determine the nature of the circulating precursor that repopulates DCs in a clinically relevant model for allo-BMT.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086899-04
Application #
7766964
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Thomas, John
Project Start
2007-02-01
Project End
2012-01-31
Budget Start
2010-02-08
Budget End
2011-01-31
Support Year
4
Fiscal Year
2010
Total Cost
$423,750
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Jiao, Jingjing; Ooka, Kohtaro; Fey, Holger et al. (2016) Interleukin-15 receptor ? on hepatic stellate cells regulates hepatic fibrogenesis in mice. J Hepatol 65:344-353
Hoeffel, Guillaume; Chen, Jinmiao; Lavin, Yonit et al. (2015) C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42:665-78
Hashimoto, Daigo; Chow, Andrew; Noizat, Clara et al. (2013) Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38:792-804
Yu, Chun I; Becker, Christian; Wang, Yuanyuan et al. (2013) Human CD1c+ dendritic cells drive the differentiation of CD103+ CD8+ mucosal effector T cells via the cytokine TGF-*. Immunity 38:818-30
Miller, Jennifer C; Brown, Brian D; Shay, Tal et al. (2012) Deciphering the transcriptional network of the dendritic cell lineage. Nat Immunol 13:888-99
Hoeffel, Guillaume; Wang, Yilin; Greter, Melanie et al. (2012) Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J Exp Med 209:1167-81
Jiao, Jingjing; Sastre, David; Fiel, Maria Isabel et al. (2012) Dendritic cell regulation of carbon tetrachloride-induced murine liver fibrosis regression. Hepatology 55:244-55
Greter, Melanie; Lelios, Iva; Pelczar, Pawel et al. (2012) Stroma-derived interleukin-34 controls the development and maintenance of langerhans cells and the maintenance of microglia. Immunity 37:1050-1060
Bogunovic, Milena; Mortha, Arthur; Muller, Paul Andrew et al. (2012) Mononuclear phagocyte diversity in the intestine. Immunol Res 54:37-49
Gautier, Emmanuel L; Chow, Andrew; Spanbroek, Rainer et al. (2012) Systemic analysis of PPAR? in mouse macrophage populations reveals marked diversity in expression with critical roles in resolution of inflammation and airway immunity. J Immunol 189:2614-24

Showing the most recent 10 out of 21 publications