The absence of tumor necrosis factor (TNF) causes lethal infection by Leishmania major in normally resistant C57BL/6J (B6.WT) mice. The underlying pathogenic mechanism of this fatal disease has so far remained elusive. We found that B6.WT mice deficient for the tnf gene (B6.TNF^−/−) displayed not only a non-healing cutaneous lesion but also a serious infection of the liver upon L. major inoculation. Infected B6.TNF^−/− mice developed an enlarged liver that showed increased inflammation. Furthermore, we detected an accumulating monocyte-derived macrophage population (CD45⁺F4/80⁺CD11b^hiLy6C^low) that displayed a M2 macrophage phenotype with high expression of CD206, arginase-1, and IL-6, supporting the notion that IL-6 could be involved in M2 differentiation. In in vitro experiments, we demonstrated that IL-6 upregulated M-CSF receptor expression and skewed monocyte differentiation from dendritic cells to macrophages. This was countered by the addition of TNF. Furthermore, TNF interfered with the activation of IL-6-induced gp130-signal transducer and activator of transcription (STAT) 3 and IL-4-STAT6 signaling, thereby abrogating IL-6-facilitated M2 macrophage polarization. Therefore, our results support the notion of a general role of TNF in the inflammatory activation of macrophages and define a new role of IL-6 signaling in macrophage polarization downstream of TNF.

Although chemokines are sufficient for chemotaxis of various cells, increasing evidence exists for their fine-tuning by selective proteolytic processing. Using a model of immune cell chemotaxis into the CNS (experimental autoimmune encephalomyelitis [EAE]) that permits precise localization of immigrating leukocytes at the blood-brain barrier, we show that, whereas chemokines are required for leukocyte migration into the CNS, additional MMP-2/9 activities specifically at the border of the CNS parenchyma strongly enhance this transmigration process. Cytokines derived from infiltrating leukocytes regulate MMP-2/9 activity at the parenchymal border, which in turn promotes astrocyte secretion of chemokines and differentially modulates the activity of different chemokines at the CNS border, thereby promoting leukocyte migration out of the cuff. Hence, cytokines, chemokines, and cytokine-induced MMP-2/9 activity specifically at the inflammatory border collectively act to accelerate leukocyte chemotaxis across the parenchymal border.

In comparison to secondary lymphoid organs, gut‐associated lymphoid tissues such as isolated lymphoid follicles (ILF) and cryptopatches (CP) have been less intensively studied. To gain a better insight into processes regulating organization and function of these structures, which are believed to participate in immune responses and extrathymic T cell development, we characterized the lymphoid structures of the murine small intestine in more detail. The size and cellular composition of small intestinal lymphoid aggregations were analyzed in C57BL/6 and BALB/c wild‐type and lymphotoxin (LT)‐deficient mice, by flow cytometry, histology and automated multi‐color immunofluorescence microscopy evaluating large coherent areas of the intestine. These evaluations demonstrate that aggregated lymphoid structures in the small intestine vary in size and cellular composition, with a majority of structures not matching the current definitions of CP or ILF. Accordingly, significant variations depending on species, age and mouse strain were observed. Furthermore, small bowel transplantation revealed a rapid exchange of B but not T cells between host and grafted tissue. Moreover, LT‐deficient animals lack any intestinal lymphoid aggregations yet possess the complete panel of intraepithelial lymphocytes (IEL). In summary, our observations disclose intestinal lymphoid aggregations as dynamic structures with a great deal of inborn plasticity and demonstrate their dispensability for the generation of IEL.

Chemokines and their cognate receptors have been identified as major factors initiating and governing cell movement and interaction. These ligands and their receptors are expressed on a wide variety of cells and act during steady-state migration as well as inflammatory recruitment. CCR6 is a non-promiscuous chemokine receptor that has only one known chemokine ligand, CCL20, and is present on B and T cells as well as dendritic cells (DCs). Two CD4⁺ T cell populations with opposing functions present in the intestines and the mesenteric lymph nodes express CCR6: the pro-inflammatory T_H17 and regulatory T_reg cells. CCL20 is also present in the intestine and is strongly up-regulated after an inflammatory stimulus. Interestingly, this ligand is also expressed by T_H17 cells, which opens up the possibility of autocrine/paracrine signaling and, consequently, a self-perpetuating cycle of recruitment, thereby promoting inflammation. Recently, CCR6 has been implicated in inflammatory bowel disease (IBD) by genome wide association studies which showed an association between SNPs in the genomic region of the CCR6 gene and the inflammation. Furthermore, recent research targeting the biological function of CCR6 indicates a significant role for this chemokine receptor in the development of chronic IBD. It is therefore possible that IBD is facilitated by a disordered regulation of T_H17 and T_reg cells due to a disruption in the CCL20-CCR6 axis and consequently disturbed mucosal homeostasis. This review will summarize the literature on CCL20-CCR6 in mucosal immunology and will analyze the role this receptor-ligand axis has in chronic IBD.

In the early phase of leishmaniasis three types of potential antigen‐presenting cells, including epidermal Langerhans cells (LC), dermal dendritic cells (DC) and inflammatory DC, are localizedat the site of infection. Therefore, it has been a central question which cell type is responsible for the initiation of a protective immune response. In the early stage of an anti‐Leishmania immune response, detectable Leishmania major antigen was localized in the paracortex of the draining lymph nodes (LN). Characterization of antigen‐positive cells showed that L. major co‐localized with DC of a CD11c⁺ CD8α^– Langerin^– phenotype. To determine the area of antigen uptake, dermis or epidermis, and to further define the type of antigen‐transporting cells, L. major was inoculated subcutaneously and concurrently LC were mobilized with fluorescein isothiocyanate (FITC). After 3 days, DC carrying L. major antigenwere always FITC^–, indicating a dermal and not an epidermal origin. Moreover, addition of L. major antigen to ex vivo isolated CD8α^– and CD8α⁺ DC fromthe draining LN of L. major‐infected C57BL/6 mice demonstrated that both DC subpopulations were able to stimulate antigen‐specific T cell proliferation in vitro. Without addition of exogenous antigen only the CD8α^– Langerin^– DC were capable of stimulating antigen‐specific T cell proliferation. Thus, we demonstrate that CD8α^– Langerin^– DC and not LC are the basis of the protective immune response to intracellular L. major parasites in vivo.