MIF is a pro-inflammatory cytokine that is produced by a wide variety of cell types including monocytes/macrophages, B- and T-lymphocytes as well as non-immunological cells like endocrine, endothelial and epithelial cells (96). In its active form it is a homotrimeric molecule that is functionally and topologically homologous to the D-dopachrome tautomerase (DDT or MIF 2) (97, 98). MIF 1 has been reported to be involved in infectious diseases, cancer, autoimmune and metabolic disorders (reviewed in (96, 99)). A wide variety
5. Discussion
of pro-inflammatory, anti-apoptotic, proliferative and also some chemokine-like functions have been ascribed to this molecule. Apart from its name-giving role in arresting macrophage migration (100, 101), one of the first reported physiologic effects of MIF was the counter-regulation of glucocorticoid suppression of immune cell responses (102). It was revealed that low concentrations of glucocorticoids induced MIF production by macrophages and helped to override glucocorticoid-mediated inhibition of inflammatory cytokine secretion in vitro and in vivo. In another report antisense RNA was used to generate MIF-deficient macrophages and to show that toll-like receptor-4 expression was dependent on MIF in this cell type. It established a critical function for MIF at the interface between innate and acquired immunity (103, 104). Further support for a pro-inflammatory function of MIF was provided by the finding that it inhibits p53-mediated apoptosis and thereby prolongs the survival of activated immune effector cells (103, 104). In addition, chemokine-like functions of MIF have been observed in inflammatory diseases and atherogenesis (85, 105).
Last not least, effects of MIF on adaptive immune responses have been reported, centering on its involvement in TH2-dependent immune reactions (106-111). An initial study showed that antibody-mediated depletion of MIF in vitro and in vivo led to diminished antigen-driven T-cell activation and antibody production (106). With the availability of MIF knockout mice, detailed analyses in models for TH2 type immune reactions were performed. In all models, significant reductions in TH2-controlled immune responses were observed with MIF knock-out mice, leading to reduced atopic reactions, reduced antibody production or increased infection (107, 109-112). These studies also showed that MIF functions at multiple levels in TH2 responses and affects multiple cell types likes macrophages, TH2 cells B-cells. Apart from its effect on signal transduction via Ii and supposedly associated proteins like CD44 (113), no molecular mechanism has been proposed, yet, by which MIF could enhance B-cell activation and BCR-triggered antigen processing and presentation on MHC II. Our data and the hypothetical model derived from them (Fig. 3) attempts to fill this gap and could serve as a basis for future investigation.
6. Summary
I
6. Summary
The B-cell receptor (BCR) transiently associates with lipid rafts upon recognition its cognate antigen. Encountering antigen induces BCR clustering and targeting to endocytic processing compartments, which are also accessed by invariant chain-MHC II complexes (Ii-MHC II). In addition, a small portion of total Ii-MHC II is present at the cell surface and described to reside in lipid rafts as well. This study was performed to investigate whether there is a lipid raft-guided interaction between BCR and Ii-MHC II that already occurs at the cell surface.
First, confocal laser scanning immunofluorescence microscopy was used to investigate the distribution of BCR and Ii-MHC II on the surface of B lymphoma cells after antibody-mediated clustering. It could be shown that, indeed, antibody-induced polyvalent clustering of BCR and Ii-MHC II lead to colocalization of both molecules at the cell surface. However, colocalization required clustering of both type of molecules. Clustering of BCR only did not redistribute Ii-MHC II to the BCR or vice versa. Macrophage migration inhibitory factor (MIF) -the physiological ligand of Ii- was found to induce colocalization of Ii-MHC II and BCR after additional antibody mediated oligomerization. The fact that Ii-MHC II and the only other protein detected to be co-clustering with BCR in this study, peptide-loaded MHC II, were reported to be lipid raft-associated suggested a lipid raft guided convergence of BCR and Ii-MHC II. This convergence was independent of F-actin and led to subsequent co-endocytosis.
Our microscopic approach was complemented by a biochemical analysis of the BCR and Ii involving detergent extraction and flotation into density gradients. The flotation analysis revealed a low tendency of clustered BCR to distribute to detergent-resistant membranes (DRMs). However, by using a rapid Brij 98 extraction method, BCR was detected in the detergent-resistant fractions, where it co-floated with Ii suggesting a lipid raft mediated interaction. This finding was confirmed by an immunoisolation experiment, in which the isolation of Ii-containing DRMs led to the co-purification of clustered BCR.
Finally, downstream signaling - the other main effect of BCR activation besides endocytosis - was found to be enhanced by coalescence with Ii as shown by increased tyrosine phosphorylation.
Our data suggest a model, in which cell-bound antigen and MIF trigger the coalescence and the endocytic co-sorting of BCR and Ii-MHC II already at the cell surface. This event might affect BCR-mediated processes like antigen processing and presentation.
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