Our overall goal is to define the development, trafficking, and functional properties of a novel gut-homing dendritic cell (DC). These mucosal """"""""?DC"""""""" reside in the intestinal lamina propria and Peyer's patches (PP), and in the bone marrow (BM). Preliminary studies have provided insights leading to the following general hypotheses: a) ?DC are distinct from conventional DC subsets in phenotype, microenvironmental localization, and development. b) They use novel trafficking cascades to home to the gut from their origin in the bone marrow. c) Gut-homing ?DC are key progenitors of intestinal DC populations including CD103+ cDC;and they can also give rise to CCR9+ plasmacytoid DC (pDC). d) ?DC may have specialized roles in mucosal immunity as evidenced by unique TLR responses and effector activities. Thus we hypothesize that ?DC are both specialized progenitors of intestinal DC, and participants in intestinal immune responses.
Aims i nclude:
Aim 1. To define the precursors and progeny of ?DC: bone marrow development and intestinal DC homeostasis. ?DC, and CCR9+ pDC are generated in Flt3L-stimulated BM cultures. To identify their origin, common DC progenitors (CDP) and other DC progenitors will be sorted from BM, and their development into DC subsets will be monitored by immunophenotyping after in vitro culture. Sorted ?DC will also be studied to evaluate their progenitor and renewal potential in vitro and in vivo. The effects of regulatory factors including retinoic acid on ?DC generation will be assessed.
Aim 2. To determine the homing properties of ?DC vs. CCR9+ pDC, and to define trafficking mechanisms involved. Short term homing assays will determine the ability of ?DC to migrate via the blood into the intestines vs. other sites, monitoring localization by flow cytometry of recovered cells from recipient tissues. Immunohistochemistry will be used to ask whether ?DC home to specific target microenvironments in the gut wall. CCR9+ pDC will be studied in parallel for comparison. Neutralizing antibodies, and/or DC from gene-targeted mice, will be used to define novel trafficking mechanisms/cascades involved.
Aim 3. To define the effects of activating (TLR ligands) and gut regulatory factors (e.g. retinoic acid) on the progenitor and immunologic activities of ?DC. In addition to their progenitor activities, ?DC stimulate T cells and display unique patterns of cytokine expression. ?DC will be assayed for maturation and altered progenitor ability in response to TLR ligands;production of immunostimulatory vs. modulatory cytokines;and education or imprinting of T cells responding to presented antigen. Regulation of their progenitor vs. immunologic activities by gut-associated factors including retinoic acid and wnts will also be assessed. Elucidating the origin, function and regulation of intestine-associated DC subsets, as proposed here, will help us understand mucosal immune homeostasis and responses to infection;and has the potential to lead to novel approaches to enhance mucosal vaccination (e.g. for HIV or rotavirus) and to control pathologic inflammation (e.g. in inflammatory bowel diseases or celiac disease).

Public Health Relevance

Dendritic cells (DC) are specialized white blood cells that control the body's balance between good (immunity to infection) and bad (for example autoimmune diseases like diabetes or inflammatory bowel disease) immune responses. We have discovered a new kind of mucosa (intestine)- associated DC that acts as a progenitor for other intestinal DC, and that may help control immune responses in the intestines. Our goal is to understand how this mucosal DC develops and gets to the intestines, what controls its differentiation into other DC types, how it responds to infection-related stimuli, and what factors control its contribution to desirable vs. damaging immune responses. In the future our findings may lead to new approaches to enhancing vaccination for AIDS or diarrheal disease, or to treating inflammatory bowel diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Rothermel, Annette L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Palo Alto Institute for Research & Edu, Inc.
Palo Alto
United States
Zip Code
Ocón, Borja; Pan, Junliang; Dinh, Theresa Thu et al. (2017) A Mucosal and Cutaneous Chemokine Ligand for the Lymphocyte Chemoattractant Receptor GPR15. Front Immunol 8:1111
Habtezion, Aida; Nguyen, Linh P; Hadeiba, Husein et al. (2016) Leukocyte Trafficking to the Small Intestine and Colon. Gastroenterology 150:340-54
Zeng, R; Bscheider, M; Lahl, K et al. (2016) Generation and transcriptional programming of intestinal dendritic cells: essential role of retinoic acid. Mucosal Immunol 9:183-93
Pan, Junliang; Dinh, Thanh Theresa; Rajaraman, Anusha et al. (2016) Patterns of expression of factor VIII and von Willebrand factor by endothelial cell subsets in vivo. Blood 128:104-9
Zabel, Brian A; Rott, Alena; Butcher, Eugene C (2015) Leukocyte chemoattractant receptors in human disease pathogenesis. Annu Rev Pathol 10:51-81
Lahl, Katharina; Sweere, Johanna; Pan, Junliang et al. (2014) Orphan chemoattractant receptor GPR15 mediates dendritic epidermal T-cell recruitment to the skin. Eur J Immunol 44:2577-81
Watchmaker, Payal B; Lahl, Katharina; Lee, Mike et al. (2014) Comparative transcriptional and functional profiling defines conserved programs of intestinal DC differentiation in humans and mice. Nat Immunol 15:98-108
Graham, Kareem L; Zhang, Jian V; Lewén, Susanna et al. (2014) A novel CMKLR1 small molecule antagonist suppresses CNS autoimmune inflammatory disease. PLoS One 9:e112925
Lee, Mike; Kiefel, Helena; LaJevic, Melissa D et al. (2014) Transcriptional programs of lymphoid tissue capillary and high endothelium reveal control mechanisms for lymphocyte homing. Nat Immunol 15:982-95
Oderup, Cecilia; LaJevic, Melissa; Butcher, Eugene C (2013) Canonical and noncanonical Wnt proteins program dendritic cell responses for tolerance. J Immunol 190:6126-34

Showing the most recent 10 out of 13 publications