Complexes of peptide and major histocompatibility complex (MHC) class II are expressed on the surface of antigen-presenting cells but their molecular organization is unknown. Here we show that subsets of MHC class II molecules localize to membrane microdomains together with tetraspan proteins, the peptide editor HLA-DM and the costimulator CD86. Tetraspan microdomains differ from other membrane areas such as lipid rafts, as they enrich MHC class II molecules carrying a selected set of peptide antigens. Antigen-presenting cells deficient in tetraspan microdomains have a reduced capacity to activate CD4+ T cells. Thus, the organization of uniformly loaded peptide-MHC class II complexes in tetraspan domains may be a very early event that determines both the composition of the immunological synapse and the quality of the subsequent T helper cell response.
The discovery of marker proteins of human blood (BECs) and lymphatic endothelial cells (LECs) has allowed researchers to isolate these cells. So far, efforts to unravel their transcriptional and functional programs made use of cultured cells only. Hence, it is unknown to which extent previously identified LEC-and BEC-specific programs are representative of the in vivo situation. Here, we define the human BEC-and LEC-specific in vivo transcriptomes by comparative genomewide expression profiling of freshly isolated cutaneous EC subsets and of non-EC skin cells (fibroblasts, mast cells, dendritic cells, epithelial cells). Interestingly, the expression of most of the newly identified EC subset-discriminating genes depends strictly on the in vivo tissue environment as revealed by comparative analyses of freshly isolated and cultured EC subsets. The identified environment-dependent, EC subsetrestricted gene expression regulates lineage fidelity, fluid exchange, and MHC class II-dependent antigen presentation.As an example for a BEC-restricted in vivo function, we show that non-activated BECs in situ, but not in vitro, assemble and display MHC class II protein complexes loaded with self-peptides. Thus, our data demonstrate the key importance of using precisely defined native IntroductionThe microvasculature is actively involved in metabolism and immune cell trafficking. Although the supply with oxygen and nutrients as well as the attraction of leukocytes is accomplished by blood vessels, the removal of extracellular fluid from the tissues and the guidance of immune cells to lymph nodes are carried out by lymphatic vessels. At the molecular level, these different functional capabilities are likely encoded by the transcriptional repertoires of blood vessel endothelial cells (BECs) and lymphatic ECs (LECs). Recently, the discovery of the LEC-specific marker proteins podoplanin (PDPN) and LYVE-1 allowed researchers to isolate and propagate BECs and LECs in vitro. 1,2 Accordingly, several techniques, including genomewide expression profiling coupled to bioinformatic approaches, have been used to identify the spectrum of genes that are expressed in cultured LECs and BECs. [3][4][5][6] However, probably as a result of technical limitations, genomewide analyses were not performed on freshly isolated ECs. Thus, it is possible that ECs, in their tissue-resident state, have a transcriptional and, thus, functional repertoire that differs from that of cultured ECs. In fact, the specialized ECs of high endothelial venules rapidly lose EC subset-defining antigen expression and morphology when these cells were placed in culture. 7 This supports that active signal exchange between ECs and the local tissue environment can also be of critical importance for the maintenance of differentiation and function of LECs and BECs.To address whether and, if so, to which extent tissue-resident LECs or BECs resemble their cultured counterparts, we established for the first time the complete transcriptomes of freshly isolated cutaneous LECs, BECs, a...
HLA-DM (DM) plays a critical role in antigen presenta
Toxicity of lipopolysaccharide (LPS) (endotoxin) is, to a large extent, mediated by the activation of monocytes/macrophages and subsequent release of monokines, such as interleukin-I (IL-1) and tumor necrosis factor alpha (TNF-a). It is known that LPS binds readily to serum lipoproteins and that LPS-lipoprotein complexes are less toxic than unbound LPS. Here we present data analyzing the impact of the LPS-serum interaction at the cellular level. By measuring IL-1 TNF-a, and IL-6, the interaction of different LPSs or lipid A with human serum could be shown to prevent the activation of human monocytes. The amounts of LPS inactivated by normal human serum did not exceed 10 ng/ml. The LPS-inactivating capacity of serum was shown to be a function of the lipoproteins. Other serum components, such as naturally occurring anti-LPS immunoglobulin G, complement, or nutritive lipids, had no significant influence in our system. Our experiments suggest that serum lipoproteins control endotoxin-induced monocyte activation and monokine release.XIX.
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