B-cells need a proper house, whereas T-cells are happy in a cave: the dependence of lymphocytes on secondary lymphoid tissues during evolution.

A fundamental tenet of immunology is that adaptive immune responses are initiated in secondary lymphoid tissues. This dogma has been challenged by several recent reports. We discuss how successful T cell-mediated immunity can be initiated outside of such dedicated structures, whereas they are required for adaptive humoral immunity. This resembles an ancient immune pathway in the oldest cold-blooded vertebrates, which lack lymph nodes and sophisticated B-cell responses including optimal affinity maturation. The T-cell, however, has retained the capacity to recognize antigen in a lymph node-free environment. Besides bone marrow and lung, the liver is one organ that can potentially serve as a surrogate lymphoid organ and could represent a remnant from the time before lymph nodes developed.

Neo-lymphoid aggregates in the adult liver can initiate potent cell-mediated immunity.

Subcutaneous immunization delivers antigen (Ag) to local Ag-presenting cells that subsequently migrate into draining lymph nodes (LNs). There, they initiate the activation and expansion of lymphocytes specific for their cognate Ag. In mammals, the structural environment of secondary lymphoid tissues (SLTs) is considered essential for the initiation of adaptive immunity. Nevertheless, cold-blooded vertebrates can initiate potent systemic immune responses even though they lack conventional SLTs. The emergence of lymph nodes provided mammals with drastically improved affinity maturation of B cells. Here, we combine the use of different strains of alymphoplastic mice and T cell migration mutants with an experimental paradigm in which the site of Ag delivery is distant from the site of priming and inflammation. We demonstrate that in mammals, SLTs serve primarily B cell priming and affinity maturation, whereas the induction of T cell-driven immune responses can occur outside of SLTs. We found that mice lacking conventional SLTs generate productive systemic CD4- as well as CD8-mediated responses, even under conditions in which draining LNs are considered compulsory for the initiation of adaptive immunity. We describe an alternative pathway for the induction of cell-mediated immunity (CMI), in which Ag-presenting cells sample Ag and migrate into the liver where they induce neo-lymphoid aggregates. These structures are insufficient to support antibody affinity maturation and class switching, but provide a novel surrogate environment for the initiation of CMI.

Dietary α-linolenic acid diminishes experimental atherogenesis and restricts T cell-driven inflammation.

AIMS: Epidemiological studies report an inverse association between plant-derived dietary α-linolenic acid (ALA) and cardiovascular events. However, little is known about the mechanism of this protection. We assessed the cellular and molecular mechanisms of dietary ALA (flaxseed) on atherosclerosis in a mouse model. METHODS AND RESULTS: Eight-week-old male apolipoprotein E knockout (ApoE(-/-)) mice were fed a 0.21 % (w/w) cholesterol diet for 16 weeks containing either a high ALA [7.3 % (w/w); n = 10] or low ALA content [0.03 % (w/w); n = 10]. Bioavailability, chain elongation, and fatty acid metabolism were measured by gas chromatography of tissue lysates and urine. Plaques were assessed using immunohistochemistry. T cell proliferation was investigated in primary murine CD3-positive lymphocytes. T cell differentiation and activation was assessed by expression analyses of interferon-γ, interleukin-4, and tumour necrosis factor α (TNFα) using quantitative PCR and ELISA. Dietary ALA increased aortic tissue levels of ALA as well as of the n-3 long chain fatty acids (LC n-3 FA) eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid. The high ALA diet reduced plaque area by 50% and decreased plaque T cell content as well as expression of vascular cell adhesion molecule-1 and TNFα. Both dietary ALA and direct ALA exposure restricted T cell proliferation, differentiation, and inflammatory activity. Dietary ALA shifted prostaglandin and isoprostane formation towards 3-series compounds, potentially contributing to the atheroprotective effects of ALA. CONCLUSION: Dietary ALA diminishes experimental atherogenesis and restricts T cell-driven inflammation, thus providing the proof-of-principle that plant-derived ALA may provide a valuable alternative to marine LC n-3 FA.

Concomitant type I IFN receptor-triggering of T cells and of DC is required to promote maximal modified vaccinia virus Ankara-induced T-cell expansion.

Virus-induced expansion of CD8(+) T cells may be promoted by type I IFN receptor (IFNAR)-triggering of T cells, depending on the pathogen tested. We studied modified vaccinia virus Ankara (MVA), a promising vaccine vector candidate, which was derived from conventional vaccinia virus (VACV) by more than 570 consecutive in vitro passages. In adoptive transfer experiments, we verified that VACV expressing the gp33 epitope of lymphocytic choriomeningitis virus (VACV(gp33)) induced largely IFNAR-independent expansion of gp33-specific T cells. On the contrary, MVA(gp33)-induced T-cell expansion was IFNAR dependent. Interestingly, under the latter conditions, T-cell activation was IFNAR independent, whereas T-cell apoptosis was enhanced in the absence of IFNAR. To address whether MVA-induced T-cell expansion was solely affected by IFNAR-triggering of T cells, expansion of endogenous T cells was studied in conditional mice with a T-cell- or DC-specific IFNAR deletion. Interestingly, both mouse strains showed moderately reduced T-cell expansion, whereas mice with a combined T-cell- and DC-specific IFNAR ablation showed massively reduced T-cell expansion similar to that of IFNAR(-/-) mice. These results are compatible with the model that IFN-inducing viruses such as MVA confer virus-specific CD8(+) T-cell expansion by concomitant IFNAR-triggering of DC and of T cells.

Histamine H1 receptor promotes atherosclerotic lesion formation by increasing vascular permeability for low-density lipoproteins.

OBJECTIVE: Enhanced endothelial permeability leading to intimal accumulation of low-density lipoproteins (LDL) stimulates the formation of atherosclerotic lesions. Histamine is known to increase vascular permeability. Whether this affects the formation of atherosclerotic lesions, however, remains elusive. METHODS AND RESULTS: Apolipoprotein E-null (ApoE(-/-)) mice treated with a histamine H1 receptor but not an H2 receptor antagonist developed 40% fewer atherosclerotic lesions in the aorta than placebo-treated controls. Similarly, genetic deletion of the H1 but not the H2 receptor resulted in a 60% reduction of lesions compared with ApoE(-/-) controls. The H1 receptor enhanced LDL permeability and lipid accumulation in the aorta, whereas plasma lipoprotein levels remained unaltered. In contrast, the H1 receptor did not affect proliferation and migration of vascular smooth muscle cells. Bone marrow transplantation confirmed that the formation of atherosclerotic lesions depended on the H1 receptor in vascular cells, whereas its presence in bone marrow-derived cells was irrelevant for plaque development. Mice expressing the H1 receptor exhibited higher levels of the chemokine (C-C motif) ligand 5 and higher numbers of macrophages and T-helper lymphocytes in plaques, higher numbers of circulating lymphocytes, and larger spleens. CONCLUSION: These data indicate that H1 but not H2 receptor activation drives the formation of atherosclerotic lesions through an increased vascular permeability for LDL, which is associated with an enhanced secondary aortic and systemic inflammation. These data open novel perspectives for the prevention and treatment of atherosclerotic vascular disease.

SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis.

AIMS: Endothelial activation, macrophage infiltration, and foam cell formation are pivotal steps in atherogenesis. Our aim in this study was to analyse the role of SIRT1, a class III deacetylase with important metabolic functions, in plaque macrophages and atherogenesis. METHODS AND RESULTS: Using partial SIRT1 deletion in atherosclerotic mice, we demonstrate that SIRT1 protects against atherosclerosis by reducing macrophage foam cell formation. Peritoneal macrophages from heterozygous SIRT1 mice accumulate more oxidized low-density lipoprotein (oxLDL), thereby promoting foam cell formation. Bone marrow-restricted SIRT1 deletion confirmed that SIRT1 function in macrophages is sufficient to decrease atherogenesis. Moreover, we show that SIRT1 reduces the uptake of oxLDL by diminishing the expression of lectin-like oxLDL receptor-1 (Lox-1) via suppression of the NF-κB signalling pathway. CONCLUSION: Our findings demonstrate protective effects of SIRT1 in atherogenesis and suggest pharmacological SIRT1 activation as a novel anti-atherosclerotic strategy by reducing macrophage foam cell formation.

Indoleamine 2,3-dioxygenase activity contributes to local immune suppression in the skin expressing human papillomavirus oncoprotein e7.

Chronic infection of anogenital epithelium with human papillomavirus (HPV) promotes development of cancer. Many pathogens evoke immunosuppressive mechanisms to enable persistent infection. We have previously shown that grafted skin expressing HPV16 E7 oncoprotein from a keratin-14 promoter (K14E7) is not rejected by a syngeneic, immunocompetent host. In this study we show that indoleamine 2,3-dioxygenase (IDO) 1, an IFN-γ-inducible immunoregulatory molecule, is more highly expressed by langerin(-ve) dermal dendritic cells (DCs) from K14E7 skin than nontransgenic control skin. Furthermore, inhibiting IDO activity using 1-methyl-dl-tryptophan (1-D/L-MT) promotes K14E7 skin graft rejection. Increased IDO1 expression and activity in K14E7 skin requires IFN-γ and invariant natural killer T (iNKT) cells, both of which have been shown to negatively regulate T-cell effector function and suppress K14E7 graft rejection. Furthermore, DCs from K14E7 skin express higher levels of IFN-γ receptor (IFN-γR) than DCs from control skin. K14E7 transgenic skin recruits significantly higher numbers of DCs, independent of IFN-γ and IFN-γR expression. Consistent with these observations in a murine model, we found higher expression of IDO1 and IFN-γ but not IDO2 in the cervical epithelium of patients with HPV-associated cervical intraepithelial neoplasia (CIN) 2/3. Our data support a hypothesis that induction of IDO1 in HPV-infected skin contributes to evasion of host immunity.

NIK signaling in dendritic cells but not in T cells is required for the development of effector T cells and cell-mediated immune responses.

The canonical NF-κB pathway is a driving force for virtually all aspects of inflammation. Conversely, the role of the noncanonical NF-κB pathway and its central mediator NF-κB-inducing kinase (NIK) remains poorly defined. NIK has been proposed to be involved in the formation of T(H)17 cells, and its absence in T(H) cells renders them incapable of inducing autoimmune responses, suggesting a T cell-intrinsic role for NIK. Upon systematic analysis of NIK function in cell-mediated immunity, we found that NIK signaling is dispensable within CD4(+) T cells but played a pivotal role in dendritic cells (DCs). We discovered that NIK signaling is required in DCs to deliver co-stimulatory signals to CD4(+) T cells and that DC-restricted expression of NIK is sufficient to restore T(H)1 and T(H)17 responses as well as cell-mediated immunity in NIK(-/-) mice. When CD4(+) T cells developed in the absence of NIK-sufficient DCs, they were rendered anergic. Reintroduction of NIK into DCs allowed developing NIK(-/-) CD4(+) T cells to become functional effector populations and restored the development of autoimmune disease. Therefore, our data suggest that a population of thymic DCs requires NIK to shape the formation of most αß CD4(+) T effector lineages during early development.