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Specific inhibition of the entry of encephalitogenic T lymphocytes into the central nervous system in multiple sclerosis would provide a means of inhibiting disease without compromising innate immune responses. We show here that targeting lymphocyte interactions with endothelial basement membrane laminins provides such a possibility. In mouse experimental autoimmune encephalomyelitis, T lymphocyte extravasation correlates with sites expressing laminin [alpha]4 and small amounts of laminin [alpha]5. In mice lacking laminin [alpha]4, laminin [alpha]5 is ubiquitously expressed along the vascular tree, resulting in marked and selective reduction of T lymphocyte infiltration into the brain and reduced disease susceptibility and severity. Vessel phenotype and immune response were not affected in these mice. Rather, laminin [alpha]5 directly inhibited integrin [alpha].sub.6][beta].sub.1] migration of T lymphocytes through laminin [alpha]4. The data indicate that T lymphocytes use mechanisms distinct from other immune cells to penetrate the endothelial basement membrane barrier, permitting specific targeting of this immune cell population., During leukocyte extravasation into inflamed tissues, cells quickly traverse the endothelial cell monolayer where they subsequently face the endothelial basement membrane. Previous data has shown that although Leukocyte transmigration of [...]

Abstract Background S100A9 has been shown to be important for the function of so called Myeloid Derived Suppressor Cells (MDSC). Cells with a similar phenotype are also involved in pro-inflammatory processes, and we therefore wanted to investigate the gene expression and function of these cells in animals that were either subjected to chronic inflammation, or inoculated with tumors. Methods CD11b+Ly6C++ and Ly6G+ cells were isolated from spleen, tumor tissue or inflammatory granulomas. S100A9, Arginase 1 and iNOS gene expression in the various CD11b+ cell populations was analyzed using Q-PCR. The suppressive activity of the CD11b+ cell populations from different donors was studied in co-culture experiments. Results S100A9 was shown to be expressed mainly in splenic CD11b+Ly6C+G+ cells both at the RNA and protein level. Arginase I and iNOS expression could be detected in both CD11b+Ly6C+Ly6G+ and CD11b+Ly6C+G-/C++G- derived from tumors or a site of chronic inflammation, but was very low in the same cell populations isolated from the spleen. CD11b+ cells isolated from mice with peritoneal chronic inflammation were able to stimulate T lymphocytes, while CD11b+ cells from mice with peritoneal tumors suppressed T cell growth. Conclusion An identical CD11b+Ly6C++G- cell population appears to have the ability to adopt immune stimulatory or immune suppressive functions dependent on the presence of a local inflammatory or tumor microenvironment. Thus, there is a functional plasticity in the CD11b+Ly6C++G- cell population that cannot be distinguished with the current molecular markers.

SMACing down TH17 cells: Currently in clinical trials for cancer therapy, second mitochondria-derived activator of caspase (SMAC) mimetics (SMs) target inhibitor of apoptosis proteins (IAPs) for degradation and sensitize tumors to tumor necrosis factor α (TNF-α)–dependent cell death (see the Focus by Dougan and Dougan). In addition, SMs synergize with immune checkpoint inhibitors to promote durable tumor immunity in mice. Using a multiomics approach, Rizk et al. found that SMs altered CD4+ T helper (TH) cell differentiation. In vitro, SMs reduced TH17 cell differentiation in an NF-κB–inducing kinase (NIK)–dependent manner and increased the differentiation of TH9 and TH2 cells producing IL-9 and IL-13. SMs reduced the production of IL-17 and disease severity in a mouse model of multiple sclerosis. This study defines how these targeted agents alter T cell function and suggests that they may have therapeutic activity in TH17 cell–driven autoimmune diseases. Second mitochondria-derived activator of caspase (SMAC) mimetics (SMs) are selective antagonists of the inhibitor of apoptosis proteins (IAPs), which activate noncanonical NF-κB signaling and promote tumor cell death. Through gene expression analysis, we found that treatment of CD4+ T cells with SMs during T helper 17 (TH17) cell differentiation disrupted the balance between two antagonistic transcription factor modules. Moreover, proteomics analysis revealed that SMs altered the abundance of proteins associated with cell cycle, mitochondrial activity, and the balance between canonical and noncanonical NF-κB signaling. Whereas SMs inhibited interleukin-17 (IL-17) production and ameliorated TH17 cell–driven inflammation, they stimulated IL-22 secretion. Mechanistically, SM-mediated activation of NF-κB–inducing kinase (NIK) and the transcription factors RelB and p52 directly suppressed Il17a expression and IL-17A protein production, as well as the expression of a number of other immune genes. Induction of IL-22 production correlated with the NIK-dependent reduction in cMAF protein abundance and the enhanced activity of the aryl hydrocarbon receptor. Last, SMs also increased IL-9 and IL-13 production and, under competing conditions, favored the differentiation of naïve CD4+ T cells into TH2 cells rather than TH17 cells. These results demonstrate that SMs shape the gene expression and protein profiles of TH17 cells and inhibit TH17 cell–driven autoimmunity. [ABSTRACT FROM AUTHOR]