The origin and development of nonlymphoid tissue CD103+ DCs

CD103+ dendritic cells (DCs) in nonlymphoid tissues are specialized in the cross-presentation of cell-associated antigens. However, little is known about the mechanisms that regulate the development of these cells. We show that two populations of CD11c+MHCII+ cells separated on the basis of CD103 and CD11b expression coexist in most nonlymphoid tissues with the exception of the lamina propria. CD103+ DCs are related to lymphoid organ CD8+ DCs in that they are derived exclusively from pre-DCs under the control of fms-like tyrosine kinase 3 (Flt3) ligand, inhibitor of DNA protein 2 (Id2), and IFN regulatory protein 8 (IRF8). In contrast, lamina propria CD103+ DCs express CD11b and develop independently of Id2 and IRF8. The other population of CD11c+MHCII+ cells in tissues, which is CD103−CD11b+, is heterogenous and depends on both Flt3 and MCSF-R. Our results reveal that nonlymphoid tissue CD103+ DCs and lymphoid organ CD8+ DCs derive from the same precursor and follow a related differentiation program.

Download Full-text

Intestinal lamina propria dendritic cells maintain T cell homeostasis but do not affect commensalism

Journal of Experimental Medicine ◽

10.1084/jem.20130728 ◽

2013 ◽

Vol 210 (10) ◽

pp. 2011-2024 ◽

Cited By ~ 106

Author(s):

Nathan E. Welty ◽

Christopher Staley ◽

Nico Ghilardi ◽

Michael J. Sadowsky ◽

Botond Z. Igyártó ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Lamina Propria ◽

Th17 Cells ◽

Intestinal Infection ◽

T Cell Homeostasis ◽

Cd11b Expression ◽

Cell Homeostasis ◽

Intestinal Lamina Propria

Dendritic cells (DCs) in the intestinal lamina propria (LP) are composed of two CD103+ subsets that differ in CD11b expression. We report here that Langerin is expressed by human LP DCs and that transgenic human langerin drives expression in CD103+CD11b+ LP DCs in mice. This subset was ablated in huLangerin-DTA mice, resulting in reduced LP Th17 cells without affecting Th1 or T reg cells. Notably, cognate DC–T cell interactions were not required for Th17 development, as this response was intact in huLangerin-Cre I-Aβfl/fl mice. In contrast, responses to intestinal infection or flagellin administration were unaffected by the absence of CD103+CD11b+ DCs. huLangerin-DTA x BatF3−/− mice lacked both CD103+ LP DC subsets, resulting in defective gut homing and fewer LP T reg cells. Despite these defects in LP DCs and resident T cells, we did not observe alterations of intestinal microbial communities. Thus, CD103+ LP DC subsets control T cell homeostasis through both nonredundant and overlapping mechanisms.

Download Full-text

Similar antigen cross-presentation capacity and phagocytic functions in all freshly isolated human lymphoid organ–resident dendritic cells

Journal of Experimental Medicine ◽

10.1084/jem.20121103 ◽

2013 ◽

Vol 210 (5) ◽

pp. 1035-1047 ◽

Cited By ~ 163

Author(s):

Elodie Segura ◽

Mélanie Durand ◽

Sebastian Amigorena

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Lymphoid Organ ◽

Lymphoid Organs ◽

Endocytic Pathway ◽

Soluble Antigen ◽

Cross Presentation ◽

Antigen Presenting ◽

Secondary Lymphoid Organs

Dendritic cells (DCs) represent a heterogeneous population of antigen-presenting cells that initiate and orient immune responses in secondary lymphoid organs. In mice, lymphoid organ–resident CD8+ DCs are specialized at cross-presentation and have developed specific adaptations of their endocytic pathway (high pH, low degradation, and high export to the cytosol). In humans, blood BDCA3+ DCs were recently shown to be the homologues of mouse CD8+ DCs. They were also proposed to cross-present antigens more efficiently than other blood DC subsets after in vitro activation, suggesting that in humans cross-presentation is restricted to certain DC subsets. The DCs that cross-present antigen physiologically, however, are the ones present in lymphoid organs. Here, we show that freshly isolated tonsil-resident BDCA1+ DCs, BDCA3+ DCs, and pDCs all cross-present soluble antigen efficiently, as compared to macrophages, in the absence of activation. In addition, BDCA1+ and BDCA3+ DCs display similar phagosomal pH and similar production of reactive oxygen species in their phagosomes. All three DC subsets, in contrast to macrophages, also efficiently export internalized proteins to the cytosol. We conclude that all freshly isolated lymphoid organ–resident human DCs, but not macrophages, display high intrinsic cross-presentation capacity.

Download Full-text

Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified.

Journal of Experimental Medicine ◽

10.1084/jem.184.5.1953 ◽

1996 ◽

Vol 184 (5) ◽

pp. 1953-1962 ◽

Cited By ~ 812

Author(s):

E Maraskovsky ◽

K Brasel ◽

M Teepe ◽

E R Roux ◽

S D Lyman ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Class Ii ◽

Terminal State ◽

T Cell Response ◽

Daily Injection ◽

Flt3 Ligand ◽

Cd11b Expression ◽

Gm Csf

Dendritic cells (DC) are the most efficient APC for T cells. The clinical use of DC as vectors for anti-tumor and infectious disease immunotherapy has been limited by their trace levels and accessibility in normal tissue and terminal state of differentiation. In the present study, daily injection of human Flt3 ligand (Flt3L) into mice results in a dramatic numerical increase in cells co-expressing the characteristic DC markers-class II MHC, CD11c, DEC205, and CD86. In contrast, in mice treated with either GM-CSF, GM-CSF plus IL-4, c-kit ligand (c-kitL), or G-CSF, class II+ CD11c+ cells were not significantly increased. Five distinct DC subpopulations were identified in the spleen of Flt3L-treated mice using CD8 alpha and CD11b expression. These cells exhibited veiled and dendritic processes and were as efficient as rare, mature DC isolated from the spleens of untreated mice at presenting allo-Ag or soluble Ag to T cells, or in priming an Ag-specific T cell response in vivo. Dramatic numerical increases in DC were detected in the bone marrow, gastro-intestinal lymphoid tissue (GALT), liver, lymph nodes, lung, peripheral blood, peritoneal cavity, spleen, and thymus. These results suggest that Flt3L could be used to expand the numbers of functionally mature DC in vivo for use in clinical immunotherapy.

Download Full-text

Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid

Journal of Experimental Medicine ◽

10.1084/jem.20070602 ◽

2007 ◽

Vol 204 (8) ◽

pp. 1775-1785 ◽

Cited By ~ 1305

Author(s):

Cheng-Ming Sun ◽

Jason A. Hall ◽

Rebecca B. Blank ◽

Nicolas Bouladoux ◽

Mohamed Oukka ◽

...

Keyword(s):

Dendritic Cells ◽

Small Intestine ◽

Retinoic Acid ◽

Immune System ◽

Lamina Propria ◽

De Novo ◽

Lymphoid Organ ◽

Oral Exposure ◽

Intestinal Immune System ◽

Cell Conversion

To maintain immune homeostasis, the intestinal immune system has evolved redundant regulatory strategies. In this regard, the gut is home to a large number of regulatory T (T reg) cells, including the Foxp3+ T reg cell. Therefore, we hypothesized that the gut environment preferentially supports extrathymic T reg cell development. We show that peripheral conversion of CD4+ T cells to T reg cells occurs primarily in gut-associated lymphoid tissue (GALT) after oral exposure to antigen and in a lymphopenic environment. Dendritic cells (DCs) purified from the lamina propria (Lp; LpDCs) of the small intestine were found to promote a high level of T reg cell conversion relative to lymphoid organ–derived DCs. This enhanced conversion by LpDCs was dependent on TGF-β and retinoic acid (RA), which is a vitamin A metabolite highly expressed in GALT. Together, these data demonstrate that the intestinal immune system has evolved a self-contained strategy to promote T reg cell neoconversion.

Download Full-text