Editorial: Functional Relevance of Tetraspanins in the Immune System

AS is supported by a Netherlands Organization for Scientific Research Grant (NWO) Gravitation Programme 2013 grant (ICI-024.002.009), a Dutch Cancer Society grant (KUN2014-6845), and was awarded an European Research Council Consolidator Grant (Secret Surface, 724281). MY-M is supported by BIO2017-86500-R Research Grant from the Spanish Ministerio de Ciencia, Innovación y Universidades. CC is supported by SAF2016-77096-R Research Grant from the Spanish Ministerio de Ciencia, Innovación y Universidade

Intracellular Galectin-9 Controls Dendritic Cell Function by Maintaining Plasma Membrane Rigidity

Biological Sciences; Molecular Biology; Cell BiologyEndogenous extracellular Galectins constitute a novel mechanism of membrane protein organization at the cell surface. Although Galectins are also highly expressed intracellularly, their cytosolic functions are poorly understood. Here, we investigated the role of Galectin-9 in dendritic cell (DC) surface organization and function. By combining functional, super-resolution and atomic force microscopy experiments to analyze membrane stiffness, we identified intracellular Galectin-9 to be indispensable for plasma membrane integrity and structure in DCs. Galectin-9 knockdown studies revealed intracellular Galectin-9 to directly control cortical membrane structure by modulating Rac1 activity, providing the underlying mechanism of Galectin-9-dependent actin cytoskeleton organization. Consequent to its role in maintaining plasma membrane structure, phagocytosis studies revealed that Galectin-9 was essential for C-type-lectin receptor-mediated pathogen uptake by DCs. This was confirmed by the impaired phagocytic capacity of Galectin-9-null murine DCs. Together, this study demonstrates a novel role for intracellular Galectin-9 in modulating DC function, which may be evolutionarily conserved

The Tetraspanin Protein CD37 Regulates IgA Responses and Anti-Fungal Immunity

Immunoglobulin A (IgA) secretion by plasma cells in the immune system is critical for protecting the host from environmental and microbial infections. However, the molecular mechanisms underlying the generation of IgA+ plasma cells remain poorly understood. Here, we report that the B cell–expressed tetraspanin CD37 inhibits IgA immune responses in vivo. CD37-deficient (CD37−/−) mice exhibit a 15-fold increased level of IgA in serum and significantly elevated numbers of IgA+ plasma cells in spleen, mucosal-associated lymphoid tissue, as well as bone marrow. Analyses of bone marrow chimeric mice revealed that CD37–deficiency on B cells was directly responsible for the increased IgA production. We identified high local interleukin-6 (IL-6) production in germinal centers of CD37−/− mice after immunization. Notably, neutralizing IL-6 in vivo reversed the increased IgA response in CD37−/− mice. To demonstrate the importance of CD37—which can associate with the pattern-recognition receptor dectin-1—in immunity to infection, CD37−/− mice were exposed to Candida albicans. We report that CD37−/− mice are evidently better protected from infection than wild-type (WT) mice, which was accompanied by increased IL-6 levels and C. albicans–specific IgA antibodies. Importantly, adoptive transfer of CD37−/− serum mediated protection in WT mice and the underlying mechanism involved direct neutralization of fungal cells by IgA. Taken together, tetraspanin protein CD37 inhibits IgA responses and regulates the anti-fungal immune response

Fatty acid metabolism in aggressive B-cell lymphoma is inhibited by tetraspanin CD37

The importance of fatty acid (FA) metabolism in cancer is well-established, yet the mechanisms underlying metabolic reprogramming remain elusive. Here, we identify tetraspanin CD37, a prognostic marker for aggressive B-cell lymphoma, as essential membrane-localized inhibitor of FA metabolism. Deletion of CD37 on lymphoma cells results in increased FA oxidation shown by functional assays and metabolomics. Furthermore, CD37-negative lymphomas selectively deplete palmitate from serum in mouse studies. Mechanistically, CD37 inhibits the FA transporter FATP1 through molecular interaction. Consequently, deletion of CD37 induces uptake and processing of exogenous palmitate into energy and essential building blocks for proliferation, and inhibition of FATP1 reverses this phenotype. Large lipid deposits and intracellular lipid droplets are observed in CD37-negative lymphoma tissues of patients. Moreover, inhibition of carnitine palmitoyl transferase 1 A significantly compromises viability and proliferation of CD37-deficient lymphomas. Collectively, our results identify CD37 as a direct gatekeeper of the FA metabolic switch in aggressive B-cell lymphoma

Tetraspanin protein expression on DC subsets.

<p>Tetraspanin protein expression on DC subsets.</p

Protein expression of tetraspanins on human DC subsets.

<p>(A) Flow cytometric analysis of total tetraspanin protein expression on fixed permeabilized DC subsets. Far left: dot plots of viable Lin-MHC II+ cells. CD1c+ DCs were identified as BDCA1+, CD141+ DCs as BDCA3+, and pDCs as BDCA4+ cells. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0184317#pone.0184317.s005" target="_blank">S2 Fig</a> for full gating strategy. Histograms of tetraspanin expression (black curve) and isotype control staining (grey curve) on gated cells depicted in the dot plots. (B) Tetraspanin expression of 3 healthy donors, geometric mean fluorescence intensity (gMFI) normalized for isotype control binding, each symbol represents one donor. P-values displayed above each plot represent the result of ANOVA to which multiple testing correction was been applied (n.s. = non-significant). * p<0.05, ** p< 0.01 ***p<0.001 by post-hoc t-testing. See also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0184317#pone.0184317.s002" target="_blank">S2 Table</a> for full results of the statistical analysis.</p

Relative mRNA expression levels of tetraspanins in murine DC subsets.

<p>Z-scored values of (A) differentially expressed genes (ANOVA p<0.05) and (B) non-differentially expressed genes (ANOVA p>0.05 and expression > 2⁵ in at least two mice in one subset). Asterisks mark genes that were selected for further analysis. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0184317#pone.0184317.s001" target="_blank">S1 Table</a> for selected probes and statistics on expression data of all members of the tetraspanin family. (C) Gene expression levels of tetraspanins in DC subsets, probe intensities are plotted, each symbol represents one mouse. P-values displayed above each plot represent the result of ANOVA to which multiple testing correction was been applied (n.s. = non-significant). * p<0.05, ** p< 0.01 ***p<0.001 by post-hoc t-testing. See also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0184317#pone.0184317.s001" target="_blank">S1 Table</a> for full results of the statistical analysis.</p