Biology subjects

Lemke, G.

Publications and source records attributed to Lemke, G..

3 recordsLinked to original sources

bioRxiv2024

Immunoglobulin A Carries Sulfated N-glycans Primarily at the Tailpiece Site -- An Oxonium-Ion-Guided Approach for Site-Specific N-glycan Identification

Sulfated N-glycans from human immunoglobulin A (IgA) were recently discovered via glycomic approaches. However, their site-specific description is still pending. Certain N-glycan structures at specific N-glycosylation sites in IgA are crucial for microbial neutralization and effector functions. For instance, sialylated N-glycans on the C-terminal tailpiece mediate anti-viral activity by interfering with sialic-acid-binding viruses. Sulfated N-glycan epitopes can be ligands for viral proteins and thus play a role in the immune response. In this study, we performed a site-specific screening for sulfated N-glycans in two commercially available human serum IgA samples employing an in-depth N-glycoproteomic approach, previously developed by us. We found evidence of complex-type and hybrid-type N-glycans containing sulfated N-acetylhexosamine (sulfated HexNAc) attached to the N-glycosylation sites in the tailpiece and the CH2 domain of both IgA subclasses. A detailed comparison of the N-glycosylation profiles of human serum IgA samples from two suppliers showed such N-glycans with sulfated HexNAc consistently in higher abundance in the tailpiece region. Surprisingly, also complex-type N-glycan compositions bearing O-acetylated sialic acid were identified in the tailpiece. These findings have not been described before for a site-specific glycopeptide analysis. Overall, our work provides a methodology for performing a dedicated site-specific search for sulfated and O-acetylated N-glycans that can be easily transferred, e.g. to human IgA derived from mucosal tissues, milk, or saliva. Our future aim is to include sulfated N-glycans into longitudinal studies of IgA N-glycosylation and to investigate their role as a biomarker and a treatment option. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/597690v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@3d0214org.highwire.dtl.DTLVardef@1537f95org.highwire.dtl.DTLVardef@dd11eeorg.highwire.dtl.DTLVardef@1c43744_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2022

A microglia-CD4+ T cell partnership generates protective anti-tumor immunity to glioblastoma

The limited efficacy of immunotherapies against glioblastoma illustrates the urgent need to better understand the interactions between the central nervous system and the immune system. Here, we showed that a protective response to CTLA-4 therapy depended on a mutualistic relationship between microglia and CD4+ T cells. Suppression of gliomas by CD4+ T cells did not require tumor-intrinsic MHC-II expression, but rather was dependent on the selective expression of MHC-II and antigen presentation by local microglia that in turn, sustained CD4+ T cell tumoricidal effector functions. CD4+ T cell secretion of IFN{gamma} made the glioma cells vulnerable to enhanced tumor surveillance and phagocytosis by microglia via the AXL/MER tyrosine kinase receptors that were necessary for tumor suppression. This work illustrates a novel partnership between CD4+ T cells and microglia that unleashes the tumoricidal properties of microglia that can be harnessed to improve immunotherapies for glioblastoma.

immunology↗

bioRxiv2019

Microglia actively remodels adult hippocampal neurogenesis through the phagocytosis secretome

During adult hippocampal neurogenesis, the majority of newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia to prevent the spillover of their intracellular contents. Here, we propose that phagocytosis is not merely a passive process of corpse removal but has an active role in maintaining adult hippocampal neurogenesis. First, we found that neurogenesis was disrupted in mice chronically deficient for two microglial phagocytosis pathways (P2Y12 and MerTK/Axl), but was transiently increased in mice in which MerTK expression was conditionally downregulated. Next, we performed a transcriptomic analysis of microglial phagocytosis in vitro and identified genes involved in metabolism, chromatin remodeling, and neurogenesis-related functions. Finally, we discovered that the secretome of phagocytic microglia limits the production of new neurons both in vivo and in vitro. Our data suggest that reprogrammed phagocytic microglia act as a sensor of local cell death, modulating the balance between cell proliferation and cell survival in the neurogenic niche, thereby supporting the long-term maintenance of adult hippocampal neurogenesis.\n\nGRAPHICAL ABSTRACT

cell biology↗