While CD28 is critical for expansion of naive T cells, recent evidence suggests that the activation of effector T cells is largely independent of CD28/B7. We suggest that ICOS, the third member of the CD28/CTLA-4 family, plays an important role in production of IL-2, IL-4, IL-5, and IFNgamma from recently activated T cells and contributes to T cell-dependent B help in vivo. Inhibition of ICOS attenuates lung mucosal inflammation induced by Th2 but not Th1 effector populations. Our data indicate a critical function for the third member of the CD28 family in T cell-dependent immune responses.

Summary Protective immunity to pathogens depends on efficient immune responses adapted to the type of pathogen and the infected tissue. Dendritic cells (DC) play a pivotal role in directing the effector T cell response to either a protective T helper type 1 (Th1) or type 2 (Th2) phenotype. Human monocyte-derived DC can be differentiated into Th1-, Th2-or Th1/Th2-promoting DC in vitro upon activation with microbial compounds or cytokines. Host defence is highly dependent on mobile leucocytes and cell trafficking is largely mediated by the interactions of chemokines with their specific receptors expressed on the surface of leucocytes. The production of chemokines by mature effector DC remains elusive. Here we assess the differential production of both inflammatory and homeostatic chemokines by monocyte-derived mature Th1/Th2-, Th1-or Th2-promoting DC and its regulation in response to CD40 ligation, thereby mimicking local engagement with activated T cells. We show that mature Th1-and Th1/Th2-, but not Th2-promoting DC, selectively express elevated levels of the inflammatory chemokines CCL2/MCP-1, CCL3/MIP-1 α , CCL4/MIP-1 β and CCL5/RANTES, as well as the homeostatic chemokine CCL19/ MIP-3 β . CCL21/6Ckine is preferentially expressed by Th2-promoting DC. Production of the Th1-attracting chemokines, CXCL9/Mig, CXCL10/IP-10 and CXCL11/I-TAC, is restricted to Th1-promoting DC. In contrast, expression of Th2-associated chemokines does not strictly correlate with the Th2-promoting DC phenotype, except for CCL22/MDC, which is preferentially expressed by Th2-promoting DC. Because inflammatory chemokines and Th1-associated chemokines are constitutively expressed by mature Th1-promoting DC and CCL22/MDC is constitutively expressed by mature Th2-promoting DC, we propose a novel role for mature DC present in inflamed peripheral tissues in orchestrating the immune response by recruiting appropriate leucocyte populations to the site of pathogen entry.

Agmatinase, which hydrolyzes agmatine to putrescine and urea, not only represents a potentially important mechanism for regulating the biological effects of agmatine in mammalian cells but also represents an alternative to ornithine decarboxylase for polyamine biosynthesis. We have isolated a full-length cDNA encoding human agmatinase whose function was confirmed by complementation in yeast. The single-copy human agmatinase gene located on chromosome 1 encodes a 352-residue protein with a putative mitochondrial targeting sequence at the NH(3)-terminus. Human agmatinase has about 30% identity to bacterial agmatinases and <20% identity to mammalian arginases. Residues required for binding of Mn(2+) at the active site in bacterial agmatinase and other members of the arginase superfamily are fully conserved in human agmatinase. Agmatinase mRNA is most abundant in human liver and kidney but also is expressed in several other tissues, including skeletal muscle and brain. Its expression in human liver is induced during hepatitis B virus infection, suggesting that agmatinase may play a role in the pathophysiology of this disease.

Scleroderma is a systemic autoimmune disease characterized by fibrosis, inflammation and vasculopathy of the skin, kidney and lung. The vasculopathy features occlusion of small arteries due vasoconstriction, intimal proliferation and thrombosis. Thrombosis results from an imbalance between coagulation and fibrinolysis. Whether thrombosis in scleroderma is primarily due to alteration in fibrinolysis or coagulation remains unclear. In this study, we investigated thrombosis in a murine GVH model of human scleroderma exhibiting an occlusive vasculopathy. We looked at fibrinolysis and coagulation biomarkers in skin, kidney and lung using qPCR and IHC. GVH skin showed microthrombi in dermis blood vessels. This was associated with an increase in a number of key regulators of fibrinolysis (PAI-1, tPA and uPAR) and coagulation (Tissue Factor, Factor VII and X), suggesting that thrombosis in GVH skin is caused by alterations in both fibrinolysis and coagulation pathways. Unlike skin, kidney and lung did not show fibrinolysis and coagulation alterations, suggesting that vasoconstriction rather than thrombosis mediates the occlusive vasculopathy in these tissues, consistent with increased endothelin-1 levels in kidney VSMCs. In conclusion, our study suggests that the GVH mouse is a useful model to study the balance of fibrinolysis and coagulation leading to thrombosis in scleroderma vasculopathy in the skin.