T(H)17 lymphocytes appear to be essential in the pathogenesis of numerous inflammatory diseases. We demonstrate here the expression of IL-17 and IL-22 receptors on blood-brain barrier endothelial cells (BBB-ECs) in multiple sclerosis lesions, and show that IL-17 and IL-22 disrupt BBB tight junctions in vitro and in vivo. Furthermore, T(H)17 lymphocytes transmigrate efficiently across BBB-ECs, highly express granzyme B, kill human neurons and promote central nervous system inflammation through CD4+ lymphocyte recruitment.
MHC-peptide complexes mediate key functions in adaptive immunity. In a classical view, MHC-I molecules present peptides from intracellular source proteins, whereas MHC-II molecules present antigenic peptides from exogenous and membrane proteins. Nevertheless, substantial crosstalk between these two pathways has been observed. We investigated the influence of autophagy on the MHC-II ligandome and demonstrated that peptide presentation is altered considerably upon induction of autophagy. The presentation of peptides from intracellular and lysosomal source proteins was strongly increased on MHC-II in contrast with peptides from membrane and secreted proteins. In addition, autophagy influenced the MHC-II antigen-processing machinery. Our study illustrates a profound influence of autophagy on the class II peptide repertoire and suggests that this finding has implications for the regulation of CD4 ؉ T cell-mediated processes.antigen processing ͉ lysosomal proteases ͉ T helper cells P eptides of foreign and self proteins are presented on MHC-I and MHC-II molecules at the cell surface and can be recognized by CD8ϩ and CD4 ϩ T lymphocytes, respectively (1, 2). From a classical point of view, MHC-I molecules present antigenic peptides derived from intracellular proteins, whereas MHC-II molecules do so for exogenous and membrane proteins (3). This phenomenon is reflected in the two major cellular breakdown pathways for proteins: proteasomal degradation, particularly relevant to the generation of MHC-I peptides (4), and degradation by the endosomal͞lysosomal system, which is responsible for the processing of MHC-II peptides (5). However, the separation of these distinct pools of source proteins is less stringent than originally believed. It is now well established that MHC-I molecules are able to present peptides derived from exogenous antigens (Ag) by a process known as cross presentation (6). On the other hand, intracellular proteins can be presented by MHC-II molecules (7,8), even though the underlying processes are less clear. It has been recently shown that peptides from cytosolic model proteins can be presented on MHC-II molecules through autophagy (9-11). Autophagy plays a role in the endosomal͞lysosomal degradation pathway and is responsible for feeding intracellular components into this pathway. It is thought to be required for normal turnover of cellular components, particularly in response to starvation (12). Against this background, we hypothesized that autophagy might mediate MHC-II presentation of intracellular Ag, meaning the contents of a cell contained within the plasma membrane, excluding large vacuoles and secretory or ingested material (Gene Ontology classifications), in general. Therefore, we performed a detailed characterization of the MHC-II ligand repertoire (ligandome) presented at the cell surface under normal conditions and after increased autophagy, leading to a comprehensive overall picture of changes in peptide processing and presentation. Materials and MethodsCell Culture and Autophagy Inducti...
Adhesion molecules of the immunoglobulin superfamily are crucial effectors of leukocyte trafficking into the central nervous system. Using a lipid raft-based proteomic approach, we identified ALCAM as an adhesion molecule involved in leukocyte migration across the blood-brain barrier (BBB). ALCAM expressed on BBB endothelium localized together with CD6 on leukocytes and with BBB endothelium transmigratory cups. ALCAM expression on BBB cells was upregulated in active multiple sclerosis and experimental autoimmune encephalomyelitis lesions. Moreover, ALCAM blockade restricted the transmigration of CD4+ lymphocytes and monocytes across BBB endothelium in vitro and in vivo and reduced the severity and delayed the time of onset of experimental autoimmune encephalomyelitis. Our findings indicate an important function for ALCAM in the recruitment of leukocytes into the brain and identify ALCAM as a potential target for the therapeutic dampening of neuroinflammation.
The clear association of Th17 cells with autoimmune pathogenicity implicates Th17 cytokines as critical mediators of chronic autoimmune diseases such as EAE. To study the impact of IL-17A on CNS inflammation, we generated transgenic mice in which high levels of expression of IL-17A could be initiated after Cre-mediated recombination. Although ubiquitous overexpression of IL-17A led to skin inflammation and granulocytosis, T cell-specific IL-17A overexpression did not have a perceptible impact on the development and health of the mice. In the context of EAE, neither the T cell-driven overexpression of IL-17A nor its complete loss had a major impact on the development of clinical disease. Since IL-17F may be able to compensate for the loss of IL-17A, we also generated IL-17F-deficient mice. This strain was fully susceptible to EAE and displayed unaltered emergence and expansion of autoreactive T cells during disease. To eliminate potential compensatory effects of either cytokine, we treated IL-17F-deficient mice with antagonistic monoclonal antibodies specific for IL-17A and found again only a minimal beneficial impact on disease development. We conclude therefore that both IL-17A and IL-17F, while prominently expressed by an encephalitogenic T cell population, may only marginally contribute to the development of autoimmune CNS disease.
Lately, IL-17-secreting Th cells have received an overwhelming amount of attention and are now widely held to be the major pathogenic population in autoimmune diseases. In particular, IL-22-secreting Th17 cells were shown to specifically mark the highly pathogenic population of self-reactive T cells in experimental autoimmune encephalomyelitis (EAE). As IL-17A itself was found to only play a minor role during the development of EAE, IL-22 is now postulated to contribute to the pathogenic function of Th17 cells. The goal of this study was to determine the role and function of IL-22 during the development of CNS autoimmunity in vivo. We found that CNS-invading encephalitogenic Th17 cells coexpress IL-22 and that IL-22 is specifically induced by IL-23 in autoimmune-pathogenic CD4+ T cells in a time- and dose-dependent manner. We next generated IL-22−/− mice, which—in contrast to the prediction that expression of inflammatory cytokines by CNS-invading T cells inevitably confers pathogenic function—turned out to be fully susceptible to EAE. Taken together, we show that self-reactive Th cells coexpress IL-17 and IL-22, but that the latter also does not appear to be directly involved in autoimmune pathogenesis of the CNS.
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