A key feature of the immune system is its ability to induce protective immunity against pathogens while maintaining tolerance towards self and innocuous environmental antigens. Recent evidence suggests that by guiding cells to and within lymphoid organs, CC-chemokine receptor 7 (CCR7) essentially contributes to both immunity and tolerance. This receptor is involved in organizing thymic architecture and function, lymph-node homing of naive and regulatory T cells via high endothelial venules, as well as steady state and inflammation-induced lymph-node-bound migration of dendritic cells via afferent lymphatics. Here, we focus on the cellular and molecular mechanisms that enable CCR7 and its two ligands, CCL19 and CCL21, to balance immunity and tolerance.

Presence and extent of bronchus-associated lymphoid tissue (BALT) is subject to considerable variations between species and is only occasionally observed in lungs of mice. Here we demonstrate that mice deficient for the chemokine receptor CCR7 regularly develop highly organized BALT. These structures were not present at birth but were detectable from day 5 onwards. Analyzing CCR7−/−/wild-type bone marrow chimeras, we demonstrate that the development of BALT is caused by alterations of the hematopoietic system in CCR7-deficient mice. These observations together with the finding that CCR7-deficient mice posses dramatically reduced numbers of regulatory T cells (T reg cells) in the lung-draining bronchial lymph node suggest that BALT formation might be caused by disabled in situ function of T reg cells. Indeed, although adoptive transfer of wild-type T reg cells to CCR7-deficient recipients resulted in a profound reduction of BALT formation, neither naive wild-type T cells nor T reg cells from CCR7−/− donors impair BALT generation. Furthermore, we provide evidence that CCR7-deficient T reg cells, although strongly impaired in homing to peripheral lymph nodes, are fully effective in vitro. Thus our data reveal a CCR7-dependent homing of T reg cells to peripheral lymph nodes in conjunction with a role for these cells in controlling BALT formation.

Little is known about mechanisms determining the homeostasis of lymphocytes within lymphoid organs. Applying different mouse models, including conditionally proficient Ccr7 gene-targeted mice, we now show that semimature steady state dendritic cells (sDCs) constitutively trafficking into lymph nodes (LNs) were essential contributors to T cell homeostasis in these organs. sDCs provided vascular endothelial growth factor known to support high endothelial venule formation, thus facilitating enhanced homing of T cells to LNs. The presence of sDCs led to increased CCL21 production in T-zone fibroblastic reticular cells. CCL21 is a ligand for CCR7 known to regulate homing as well as retention of T cells in LNs. In addition, we provide evidence that CCL21 binds to the surface of DCs via its heparin-binding domain, further explaining why T cells leave LNs more rapidly in the absence of sDCs. Together, these data reveal multiple roles for sDCs in regulating T cell homeostasis in LNs.

Development of autoimmunity is a multi‐factorial process involving genetic predisposition as well as environmental and stochastic factors. Although the mechanisms responsible for the initiation of autoimmunity remain only partially understood, several studies have demonstrated that genetic predisposition plays a major role in this process. In the present study, we analyzed the influence of CCR7 signaling in the development of autoimmunity, because this chemokine receptor is essentially involved in the functional organization of thymus architecture. We demonstrate that CCR7‐deficient mice are prone to develop generalized multi‐organ autoimmunity. The autoimmune phenotype of CCR7–/– mice encompasses the presence of lymphocyte infiltrates in several peripheral organs, circulating autoantibodies against a multitude of tissue‐specific antigens and IgG deposition on renal glomeruli. Additionally, CCR7‐deficient mice show increased susceptibility to streptozotocin‐induced diabetes and spontaneously display signs of chronic autoimmune renal disease. Thus, this study identifies CCR7 as a genetic factor involved in the regulation of autoimmunity.

The chemokine receptor CCR7 has been implicated in maintenance of thymus morphology and establishment of tolerance to self-antigens. In this study, we provide direct evidence that negative selection of maturing thymocytes is defective in CCR7-deficent mice. Impaired negative selection was observed after TCR/CD3 complex stimulation in vivo as well as in vitro and was prominent in both doublepositive and semimature single positive cells (CD4 ؉ CD8 ؊ CD24 high ). It is noteworthy that thymocytes of CCR7 ؊/؊ mice display defective negative selection in response to endogenous superantigens, demonstrating that the defect also occurs under physiological conditions. Disturbed negative selection was correlated with delayed activation kinetics and decreased calcium flux response of CCR7 ؊/؊ thymocytes after in vitro TCR/CD3 stimulation, suggesting that an impaired response of CCR7 ؊/؊ thymocytes via TCR-mediated signaling is responsible for defective negative selection in these mice. IntroductionCCR7 is a major regulator of the immune system, orchestrating a broad spectrum of fundamental processes ranging from lymphoid organ development to induction of defensive immune responses as well as oral tolerance. [1][2][3] An important role for CCR7 in thymus compartmentalization and coordination of migratory events during thymopoiesis has been recently demonstrated. 4,5 Mice deficient in CCR7 or in its ligands CCL19 and CCL21-ser (plt/plt mice 6,7 ) display altered thymus architecture, impaired T-cell development, and decreased numbers of thymocytes. 4,5 Alterations of the thymus architecture are frequently observed in mice suffering from autoimmunity, such as mice deficient in the transcriptional regulator autoimmune regulator (Aire) and nonobese diabetic (NOD) mice. 8,9 In these strains, autoimmunity correlates with breakdown of central tolerance, although in NOD mice peripheral tolerance seems to be affected as well. [10][11][12] It has been noted previously that lack of CCR7 signaling is associated with the manifestation of autoimmunity to lachrymal and salivary glands. 13 Expanding this view, we recently demonstrated that CCR7-deficient mice in fact display a more generalized autoimmune phenotype affecting several organs. 14 These observations raised the possibility that CCR7-deficiency affects induction of central tolerance.The hallmark of central tolerance is the negative selection of potentially self-reactive thymocytes. This process guarantees the generation of a self-tolerant peripheral T-cell repertoire. The major mechanism of negative selection is clonal deletion. During this process, thymocytes reacting strongly to self-peptide-self-MHC complexes are eliminated. 15,16 Several studies using well characterized in vivo and in vitro models of negative selection suggest that clonal deletion can occur in all developmental stages of thymocytes, including double-negative, double-positive (DP), and singlepositive (SP). 15,[17][18][19][20] However, it is widely accepted that (for thymocytes expressing an MHC class II-restric...

Nonalcoholic steatohepatitis (NASH) is induced by steatosis and metabolic inflammation. While involvement of the innate immune response has been shown, the role of the adaptive immune response in NASH remains controversial. Likewise, the role of regulatory T cells (Treg) in NASH remains unclear although initial clinical trials aim to target these regulatory responses. High‐fat high‐carbohydrate (HF‐HC) diet feeding of NASH‐resistant BALB/c mice as well as the corresponding recombination activating 1 (Rag)‐deficient strain was used to induce NASH and to study the role of the adaptive immune response. HF‐HC diet feeding induced strong activation of intrahepatic T cells in BALB/c mice, suggesting an antigen‐driven effect. In contrast, the effects of the absence of the adaptive immune response was notable. NASH in BALB/c Rag1−/− mice was substantially worsened and accompanied by a sharp increase of M1‐like macrophage numbers. Furthermore, we found an increase in intrahepatic Treg numbers in NASH, but either adoptive Treg transfer or anti‐cluster of differentiation (CD)3 therapy unexpectedly increased steatosis and the alanine aminotransferase level without otherwise affecting NASH. Conclusion: Although intrahepatic T cells were activated and marginally clonally expanded in NASH, these effects were counterbalanced by increased Treg numbers. The ablation of adaptive immunity in murine NASH led to marked aggravation of NASH, suggesting that Tregs are not regulators of metabolic inflammation but rather enhance it.

Nose-associated lymphoid tissue (NALT) in the rodent upper respiratory tract develops postnatally and is considered to be independent of several factors known to be involved in the organogenesis of LN and Peyer's patches (PP). In this study we demonstrate that at least two different pathways result in NALT development. Following NALT anlage formation the intrinsic pathway relies on a signaling cascade including those mediated through the chemokine receptor CXCR5 and the lymphotoxin b receptor (LTbR). This allows for the formation of high endothelial venules and thereby the recruitment of lymphocytes into NALT. Alternatively, high endothelial venule formation and lymphocyte recruitment can be induced in the NALT anlage by environmental signals, which are independent of LT-bR and chemokine receptor CXCR5 signaling but in part rely on CD40 ligand. Thus, our study identifies a novel mechanism that facilitates the rescue of NALT development at late stages in adult life independent of the canonical LTbR-CXCR5 signaling axis.Key words: Chemokines . Developmental immunology . Lymphoid organs Supporting Information available online IntroductionMucosal surfaces are equipped with dedicated mucosa-associated lymphoid tissues that facilitate the induction of mucosal immune responses. Nose-associated lymphoid tissue (NALT) in the rodent upper respiratory tract belongs to these specialized structures [1]. Due to its close proximity to entry sites of foreign and infectious agents NALT is an important inductive tissue for the generation of long lasting mucosal immunity in the upper respiratory tract and in the oral cavity [2][3][4][5][6]. NALT represents a paired lymphoid structure localized cranially to the soft palate at the bifurcated pharyngeal duct of rodents. Each part of the organ is composed of follicle-associated epithelium, high endothelial venules (HEV), T-and B-cell-enriched areas as well as DC [2].In contrast to most secondary lymphoid organs, the development of NALT initiates postnatally [7][8][9]. Furthermore, NALT undergoes substantial changes at weaning and its structural differentiation seems to be completed 6 wk after birth indicating that NALT development might be influenced by environmental stimuli [7]. The conventional model of secondary lymphoid organ development presumes the interplay between stromal organizer cells and CD45 receptors CXCR5 and CCR7. NALT development is initiated independently of the majority of factors known to be involved in the interaction of stromal organizer and LTi cells, such as LTa, LTb, LTbR, TNF, TNFRp55, IL7-R, RORg, TRANCE, CXCL13, CCL19 and CCL21 [8][9][10][11], [8,9,12,13]. The only molecule identified so far and believed to be essential for the initiation of the NALT anlage formation is the transcriptional regulator ''inhibitor of DNA binding 2'' (Id2) [10]. Although LTi cells are missing in Id2 À/À mice it seems unlikely that the lack of this cell population is responsible for the absence of NALT in Id2 À/À mice as NALT develops in RORg À/À mice, which also lack LTi cells ...

Background: The chemokine receptor CCR7 is a key organizer of the immune system. Gene targeting in mice revealed that Ccr7-deficient animals are severely impaired in the induction of central and peripheral tolerance. Due to these defects, Ccr7-deficient mice spontaneously develop multi-organ autoimmunity showing symptoms similar to those observed in humans suffering from connective tissue autoimmune diseases. However, it is unknown whether mutations of CCR7 are linked to autoimmunity in humans.