Lymphoid Organ-Resident Dendritic Cells Exhibit Unique Transcriptional Fingerprints Based on Subset and Site

Lymphoid organ-resident DC subsets are thought to play unique roles in determining the fate of T cell responses. Recent studies focusing on a single lymphoid organ identified molecular pathways that are differentially operative in each DC subset and led to the assumption that a given DC subset would more or less exhibit the same genomic and functional profiles throughout the body. Whether the local milieu in different anatomical sites can also influence the transcriptome of DC subsets has remained largely unexplored. Here, we interrogated the transcriptional relationships between lymphoid organ-resident DC subsets from spleen, gut- and skin-draining lymph nodes, and thymus of C57BL/6 mice. For this purpose, major resident DC subsets including CD4 and CD8 DCs were sorted at high purity and gene expression profiles were compared using microarray analysis. This investigation revealed that lymphoid organ-resident DC subsets exhibit divergent genomic programs across lymphoid organs. Interestingly, we also found that transcriptional and biochemical properties of a given DC subset can differ between lymphoid organs for lymphoid organ-resident DC subsets, but not plasmacytoid DCs, suggesting that determinants of the tissue milieu program resident DCs for essential site-specific functions

Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes

Fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (LECs) are nonhematopoietic stromal cells of lymphoid organs. They influence the migration and homeostasis of naive T cells; however, their influence on activated T cells remains undescribed. Here we report that FRCs and LECs inhibited T cell proliferation through a tightly regulated mechanism dependent on nitric oxide synthase 2 (NOS2). Expression of NOS2 and production of nitric oxide paralleled the activation of T cells and required a tripartite synergism of interferon-γ, tumor necrosis factor and direct contact with activated T cells. Notably, in vivo expression of NOS2 by FRCs and LECs regulated the size of the activated T cell pool. Our study elucidates an as-yet-unrecognized role for the lymph node stromal niche in controlling T cell responses

A novel form of 4-1BBL has better immunomodulatory activity than an agonistic anti-4-1BB Ab without Ab-associated severe toxicity

7th European Workshop on Optical Fibre Sensors (EWOFS'2019), , 01/10/2019-04/10/2019, Limassol, Chipre.We propose a fully distributed optical fiber sensor capable of performing spectrally-resolved detection of visible light radiation. The sensor is based on monitoring the temperature change between two optical fibers with different coating colors. In our implementation, the temperature is simultaneously monitored in a black-coated fiber (which is highly sensitive to all input wavelengths) and a color-coated fiber, which basically acts as an optical stop-band filter for a certain input color. By comparing the temperature behavior attained for each fiber, it is possible to obtain information of the wavelength/color of a given optical radiation present in the environment. Suitable calibration could lead to distributed colorimetry measurements.European CommissionMinisterio de Economía y CompetitividadComunidad de Madri

In vivo discovery of immunotherapy targets in the tumour microenvironment

Recent clinical trials showed that targeting of inhibitory receptors on T cells induces durable responses in a subset of cancer patients, despite advanced disease. However, the regulatory switches controlling T-cell function in immunosuppressive tumours are not well understood. Here we show that such inhibitory mechanisms can be systematically discovered in the tumour microenvironment. We devised an in vivo pooled short hairpin RNA (shRNA) screen in which shRNAs targeting negative regulators became highly enriched in murine tumours by releasing a block on T-cell proliferation upon tumour antigen recognition. Such shRNAs were identified by deep sequencing of the shRNA cassette from T cells infiltrating tumour or control tissues. One of the target genes was Ppp2r2d, a regulatory subunit of the PP2A phosphatase family. In tumours, Ppp2r2d knockdown inhibited T-cell apoptosis and enhanced T-cell proliferation as well as cytokine production. Key regulators of immune function can therefore be discovered in relevant tissue microenvironments.National Institutes of Health (U.S.) (Transformative Research Award 1R01CA173750)Dana-Farber/Harvard Cancer Center (Bridge Project)Lustgarten FoundationNovartis Institutes of Biomedical ResearchNational Cancer Institute (U.S.) (Koch Institute Support Grant P30-CA14051)American Cancer Society (John W. Thatcher, Jr Postdoctoral Fellowship in Melanoma Research)Breast Cancer Research Foundation (Terri Brodeur Breast Cancer Foundation Postdoctoral Fellowship)National Institutes of Health (U.S.) (NIH T32 grant AI07386