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Ludewig, B.

Publications and source records attributed to Ludewig, B..

2 recordsLinked to original sources
bioRxiv2019

Perinatal Programming of Mucosal Stromal Cell Identity by the Lymphotoxin Pathway Regulates Mucosal Immune Responses in the Adult

Redundant mechanisms support IgA responses to intestinal antigens. These include multiple priming sites (mesenteric lymph nodes (MLN), Peyers patches and isolated lymphoid follicles) and various cytokines that promote class switch to IgA, even in the absence of T cells. In spite of these back-up mechanisms, vaccination against enteric pathogens such as Rotavirus has limited success in some populations. Genetic and environmental signals experienced during early life are known to influence mucosal immunity, yet the mechanisms for how these exposures operate remain unclear. Here we used Rotavirus infection to follow antigen-specific IgA responses through time and in different gut compartments. Using genetic and pharmacological approaches, we tested the role of a pathway known to support IgA responses (Lymphotoxin - LT) at different developmental stages. We found that LT-beta receptor (LT{beta}R) signalling in utero programs intestinal IgA responses in adulthood by affecting antibody class switch recombination to IgA and subsequent generation of IgA antibody-secreting cells within an intact MLN. In addition, in utero LT{beta}R signalling dictates the phenotype and function of MLN stromal cells in order to support IgA responses in the adult. Collectively, our studies uncover new mechanistic insights into how in utero LT{beta}R signalling impacts mucosal immune responses during adulthood. One Sentence SummaryEarly life LT{beta}R signalling is critical for programming the mesenteric lymph node stromal cell environment, impacting both antibody isotype switching to IgA and the differentiation of IgA+ antibody secreting cells. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=190 HEIGHT=200 SRC="FIGDIR/small/557652v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@4780dborg.highwire.dtl.DTLVardef@5cbe85org.highwire.dtl.DTLVardef@e0465eorg.highwire.dtl.DTLVardef@2bcae6_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗
bioRxiv2018

Time-resolved systems analysis reveals a critical role of XCR1+ 1 dendritic cells in the maintenance of effector T cells during chronic viral infection

Upon a viral infection, the host immune system attempts to eradicate the virus. However, once the infection threat seems overwhelming, the infected host actively shuts down effector responses to reduce immunopathology. The price to pay for this is the establishment of a chronic infection that is only partially controlled by a lower level immune response. The genetic networks underlying this infection fate decision and the immune adaptation to the lower level response are not well understood. Here we used an integrated approach of gene coexpression network analysis of time-resolved splenic transcriptomes and immunological analysis to characterize the host response to acute and chronic lymphocytic choriomeningitis virus (LCMV) infections. We found first, an early attenuation of inflammatory monocyte/macrophage prior to the onset of T cell exhaustion and second, a critical role of the XCL1-XCR1 communication axis during the functional adaptation of the T cell response to the chronic infection state. These findings not only reveal an important feedback mechanism that couples T cell exhaustion with the maintenance of a lower level of effector T cell response but also suggest therapy options to better control virus levels during the chronic infection phase.\n\nAuthor SummaryThe outcomes of viral infections are the result of dynamic interplays between infecting viruses and induced host responses. They can be categorized as either acute or chronic depending on temporal virus-host relationships. Chronic infections are associated with immune exhaustion, a partial shut-down of effector responses. The processes underlying infection fate decisions are incompletely understood. Here we analyzed, on a systems level, infection-fate-specific gene signatures and the resulting adaptive processes of the host. We used the well-established lymphocytic choriomeningitis virus infection mouse model which has been instrumental to detect many fundamental processes in the virus-immune system crosstalk that are also relevant in human infections. We show an early attenuation of macrophage-mediated inflammation and an involvement of cross-presenting dendritic cells in the maintenance of an antiviral cytotoxic T cell response and virus control in the chronic infection phase. Together our data demonstrate a delicate adaptation process towards a chronic virus infection with both immunosuppressive and immunostimulatory processes. We fill a knowledge gap regarding the mechanisms of effector T cell maintenance and provide a new rational for targeted therapeutic vaccination.

immunology↗