Migratory, and not lymphoid-resident, dendritic cells maintain peripheral self-tolerance and prevent autoimmunity via induction of iTreg cells

Abstract There is evidence that dendritic cells (DCs) induce peripheral tolerance. Nevertheless, it is not known whether immature DCs in general are able to tolerize CD4+ T cells or if this is a prerogative of specialized subtypes. Here we show that, when autoantigen presentation is extended to all conventional mouse DCs, immature lymphoid tissue resident DCs are unable to induce autoantigen-specific regulatory T (iTreg) cell conversion. In contrast, this is an exclusive prerogative of steady-state migratory DCs. Because only lymph nodes host migratory DCs, iTreg cells develop and are retained solely in lymph nodes, and not in the spleen. Mechanistically, in cutaneous lymph nodes, DC-derived CCL22 contributes to the retention of iTreg cells. The importance of the local generation of iTreg cells is emphasized by their essential role in preventing autoimmunity.

Download Full-text

Lymph-migrating, tissue-derived dendritic cells are minor constituents within steady-state lymph nodes

Journal of Experimental Medicine ◽

10.1084/jem.20081430 ◽

2008 ◽

Vol 205 (12) ◽

pp. 2839-2850 ◽

Cited By ~ 160

Author(s):

Claudia Jakubzick ◽

Milena Bogunovic ◽

Anthony J. Bonito ◽

Emma L. Kuan ◽

Miriam Merad ◽

...

Keyword(s):

Dendritic Cells ◽

Lymph Node ◽

Steady State ◽

Lymph Nodes ◽

Lymphatic Vessels ◽

Inflammatory Stimulus ◽

Major Fraction ◽

Reporter Mouse ◽

Relationship Of ◽

The Relationship

Observations that dendritic cells (DCs) constitutively enter afferent lymphatic vessels in many organs and that DCs in some tissues, such as the lung, turnover rapidly in the steady state have led to the concept that a major fraction of lymph node DCs are derived from migratory DCs that enter the lymph node through upstream afferent lymphatic vessels. We used the lysozyme M–Cre reporter mouse strain to assess the relationship of lymph node and nonlymphoid organ DCs. Our findings challenge the idea that a substantial proportion of lymph node DCs derive from the upstream tissue during homeostasis. Instead, our analysis suggests that nonlymphoid organ DCs comprise a major population of DCs within lymph nodes only after introduction of an inflammatory stimulus.

Download Full-text

Dendritic Cells Induce Peripheral T Cell Unresponsiveness under Steady State Conditions in Vivo

Journal of Experimental Medicine ◽

10.1084/jem.194.6.769 ◽

2001 ◽

Vol 194 (6) ◽

pp. 769-780 ◽

Cited By ~ 1276

Author(s):

Daniel Hawiger ◽

Kayo Inaba ◽

Yair Dorsett ◽

Ming Guo ◽

Karsten Mahnke ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Steady State ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Interferon Γ ◽

Peripheral Tolerance ◽

Antigen Delivery

Dendritic cells (DCs) have the capacity to initiate immune responses, but it has been postulated that they may also be involved in inducing peripheral tolerance. To examine the function of DCs in the steady state we devised an antigen delivery system targeting these specialized antigen presenting cells in vivo using a monoclonal antibody to a DC-restricted endocytic receptor, DEC-205. Our experiments show that this route of antigen delivery to DCs is several orders of magnitude more efficient than free peptide in complete Freund's adjuvant (CFA) in inducing T cell activation and cell division. However, T cells activated by antigen delivered to DCs are not polarized to produce T helper type 1 cytokine interferon γ and the activation response is not sustained. Within 7 d the number of antigen-specific T cells is severely reduced, and the residual T cells become unresponsive to systemic challenge with antigen in CFA. Coinjection of the DC-targeted antigen and anti-CD40 agonistic antibody changes the outcome from tolerance to prolonged T cell activation and immunity. We conclude that in the absence of additional stimuli DCs induce transient antigen-specific T cell activation followed by T cell deletion and unresponsiveness.

Download Full-text

CCR7 Essentially Contributes to the Homing of Plasmacytoid Dendritic Cells to Lymph Nodes under Steady-State As Well As Inflammatory Conditions

The Journal of Immunology ◽

10.4049/jimmunol.1002598 ◽

2011 ◽

Vol 186 (6) ◽

pp. 3364-3372 ◽

Cited By ~ 74

Author(s):

Sebastian Seth ◽

Linda Oberdörfer ◽

Rebecca Hyde ◽

Kirstin Hoff ◽

Verena Thies ◽

...

Keyword(s):

Dendritic Cells ◽

Steady State ◽

Lymph Nodes ◽

Plasmacytoid Dendritic Cells ◽

Inflammatory Conditions

Download Full-text

Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity

Journal of Experimental Medicine ◽

10.1084/jem.20082394 ◽

2009 ◽

Vol 206 (3) ◽

pp. 549-559 ◽

Cited By ~ 376

Author(s):

Caspar Ohnmacht ◽

Andrea Pullner ◽

Susan B.S. King ◽

Ingo Drexler ◽

Stefanie Meier ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Steady State ◽

Cd4 T Cells ◽

Tolerance Induction ◽

Immunological Tolerance ◽

Peripheral Tissues ◽

Reduced Body ◽

Self Tolerance ◽

Single Positive

Lack of immunological tolerance against self-antigens results in autoimmune disorders. During onset of autoimmunity, dendritic cells (DCs) are thought to be critical for priming of self-reactive T cells that have escaped tolerance induction. However, because DCs can also induce T cell tolerance, it remains unclear whether DCs are required under steady-state conditions to prevent autoimmunity. To address this question, we crossed CD11c-Cre mice with mice that express diphtheria toxin A (DTA) under the control of a loxP-flanked neomycin resistance (neoR) cassette from the ROSA26 locus. Cre-mediated removal of the neoR cassette leads to DTA expression and constitutive loss of conventional DCs, plasmacytoid DCs, and Langerhans cells. These DC-depleted (ΔDC) mice showed increased frequencies of CD4 single-positive thymocytes and infiltration of CD4 T cells into peripheral tissues. They developed spontaneous autoimmunity characterized by reduced body weight, splenomegaly, autoantibody formation, neutrophilia, high numbers of Th1 and Th17 cells, and inflammatory bowel disease. Pathology could be induced by reconstitution of wild-type (WT) mice with bone marrow (BM) from ΔDC mice, whereas mixed BM chimeras that received BM from ΔDC and WT mice remained healthy. This demonstrates that DCs play an essential role to protect against fatal autoimmunity under steady-state conditions.

Download Full-text

Lymphoid tissue–specific homing of bone marrow–derived dendritic cells

Blood ◽

10.1182/blood-2009-02-204321 ◽

2009 ◽

Vol 113 (26) ◽

pp. 6638-6647 ◽

Cited By ~ 46

Author(s):

Rémi J. Creusot ◽

Shahriar S. Yaghoubi ◽

Pearl Chang ◽

Justine Chia ◽

Christopher H. Contag ◽

...

Keyword(s):

Bone Marrow ◽

Dendritic Cells ◽

Lymph Nodes ◽

Lymphoid Tissue ◽

Cellular Therapy ◽

Autoimmune Diabetes ◽

Specific Treatment ◽

Lymphoid Tissues ◽

Murine Bone Marrow ◽

Therapeutic Tools

Abstract Because of their potent immunoregulatory capacity, dendritic cells (DCs) have been exploited as therapeutic tools to boost immune responses against tumors or pathogens, or dampen autoimmune or allergic responses. Murine bone marrow–derived DCs (BM-DCs) are the closest known equivalent of the blood monocyte-derived DCs that have been used for human therapy. Current imaging methods have proven unable to properly address the migration of injected DCs to small and deep tissues in mice and humans. This study presents the first extensive analysis of BM-DC homing to lymph nodes (and other selected tissues) after intravenous and intraperitoneal inoculation. After intravenous delivery, DCs accumulated in the spleen, and preferentially in the pancreatic and lung-draining lymph nodes. In contrast, DCs injected intraperitoneally were found predominantly in peritoneal lymph nodes (pancreatic in particular), and in omentum-associated lymphoid tissue. This uneven distribution of BM-DCs, independent of the mouse strain and also observed within pancreatic lymph nodes, resulted in the uneven induction of immune response in different lymphoid tissues. These data have important implications for the design of systemic cellular therapy with DCs, and in particular underlie a previously unsuspected potential for specific treatment of diseases such as autoimmune diabetes and pancreatic cancer.

Download Full-text

The effects of dietary lipids on dendritic cells in perinodal adipose tissue during chronic mild inflammation

British Journal Of Nutrition ◽

10.1079/bjn20041147 ◽

2004 ◽

Vol 91 (6) ◽

pp. 883-892 ◽

Cited By ~ 25

Author(s):

Christine A. Mattacks ◽

Dawn Sadler ◽

Caroline M. Pond

Keyword(s):

Dendritic Cells ◽

Adipose Tissue ◽

Lymph Nodes ◽

Fish Oil ◽

Lymphoid Tissue ◽

Sunflower Seed ◽

Seed Oil ◽

Dietary Lipids ◽

Sunflower Seed Oil ◽

Popliteal Lymph Nodes

The effects of dietary lipids on the abundance of dendritic cells in adipose tissue in anatomically defined relationships to chronically inflamed lymph nodes were investigated in mature male rats fed plain chow or chow plus 20 % sunflower-seed or fish oil. The popliteal lymph nodes were stimulated by local subcutaneous injection of 20 μg lipopolysaccharide to both hindlegs three times/week for 2 weeks. The masses of the major adipose depots and the numbers of dendritic cells emerging from perinodal adipose tissue and samples 5 and 10 mm from the popliteal lymph nodes were measured, and those from omental and mesenteric adipose tissue around and remote from lymphoid tissue, and mesenteric and popliteal lymph nodes. Dendritic cells were most numerous in the perinodal adipose tissue, with the corresponding ‘remote’ samples containing 25–50 % fewer such cells under all conditions studied. Dietary sunflower-seed oil increased the numbers of dendritic cells by about 17 % in all adipose samples and fish oil reduced the numbers in perinodal tissue by about 5 %. The fish-oil diet diminished responses of the intra-abdominal adipose depots to local stimulation of the popliteal node. Correlations in dendritic cell numbers were stronger between perinodal samples from different depots than between remote and perinodal samples from the same depot and after the sunflower-seed-oil diet compared with fish oil. These data show that dietary lipids modulate the number of dendritic cells in lymphoid tissue-containing adipose depots and support the hypothesis that perinodal adipose tissue interacts locally with lymphoid cells.

Download Full-text