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Paper Reading Regulatory T cells mediate specific suppression by depleting peptide–MHC class II from dendritic cells  Billur Akkaya 1,8 *, Yoshihiro Oya 1,2,8 , Munir Akkaya 3 , Jafar Al Souz 1 , Amanda H. Holstein 1,6 , Olena Kamenyeva 4 , Juraj Kabat 4 , Ryutaro Matsumura 2 , David W. Dorward 5 , Deborah D. Glass 1,7 and Ethan M. Shevach Nat Immunol. 2019 Regulatory T cells (Tregcells) can activate multiple suppressive mechanisms in vitro after activation via the T cell antigen receptor, resulting in antigen-independent suppression. However, it remains unclear whether similar pathways operate in vivo. In this paper, the author describes a novel pathway for antigen-specific Tregcell mediated suppression. Firstly, they characterized the interactions of freshly isolated 5CC7 T naive cells, 5CC7 activated T cells and 5CC7 iTregcells with moth cytochrome C (MCC) 88–103-pulsed DCs using scanning electron microscopy (SEM) and transmission electron microscopy (TEM) after 2 h of coculture in vitro.Tilted SEM images of the T cell–DC binding sites revealed an average of three to nine membrane-fusion nanodomains per T cell–DC couple. To further analyze the mechanism of suppression mediated by antigen-specific iTregcells, they precultured iTregcells with DCs pulsed with both OVA323–339and GP61–80, depleted the iTregcells from the DCs and evaluated the capacity of the treated DCs to stimulate TCR-transgenic T naive cells. DCs precultured with OT-II iTregcells failed to activate OT-II T cells but retained the capacity to activate SMARTA T cells. Similarly, DCs precultured with SMARTA iTregcells failed to activate SMARTA T cells but stimulated OT-II T cells as efficiently as control DCs did. Then they labeled DC membranes with the lipophilic dye PKH26 and pulsed them with MCC88–103. DCs were then cultured with 5CC7 T naive cells, T activated cells or iTregcells for 18 h. 5CC7 iTregcells acquired a greater amount of the DC membrane than did T naive cells or T activated cells, as measured by the increase in their PKH26 fluorescence intensity. What’s more, they could easily detect surface molecules involved in the immune synapse, such as MHCII, CD86, ICOSL. To visualize the acquisition of antigen-specific pMHCII, the author made use of a monoclonal antibody D4 which aims to the complex of MCC88–103and the MHCII molecule I-E k24 and detects them by TEM. Only iTregcells had intense DC contacts where they engulfed parts of the DC membrane. In conclusion, antigen-specific Tregcells formed strong interactions with DCs, strong binding resulted in the removal of the complex of cognate peptide and major histocompatibility complex class II (pMHCII) from the DC surface, reducing the capacity of DCs to present antigen. doi: 10.1038/s41590-018-0280-2 Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-g and IL-12  Christopher S. Garris, 1,2,12 Sean P. Arlauckas, 1,3,12 Rainer H. Kohler, 1 Marcel P. Trefny, 4,5 Seth Garren, 1 Ce´cile Piot, 1 Camilla Engblom, 1 Christina Pfirschke, 1 Marie Siwicki, 1,2 Jeremy Gungabeesoon, 1 Gordon J. Freeman, 6 Sarah E. Warren, SuFey Ong, 7 Erica Browning, 8 Christopher G. Twitty, 8 Robert H. Pierce, 8 Mai H. Le, 8 Alain P. Algazi, 9 Adil I. Daud, 9 Sara I. Pai, 10 Alfred Zippelius, 4 Ralph Weissleder, 1,3,11 and Mikael J. Pittet 1,3,13, * Immunity. 2018 Immune checkpoint blockade has emerged as a critical treatment against various cancer types, however, we still have a limited understanding of how immune checkpoint blockers engage complex tumor microenvironments and which mechanisms define treatment success. In this paper, the author showed that effective anti-PD-1 immunotherapy requires intratumoral dendritic cells (DCs) producing IL-12. Anti-PD-1 indirectly activates DCs through IFN-g released from drug-activated T cells. Firstly, using IFN-γ-IRES-YFP and IL12-IRES-YFP reporter mice, they tracked IFN-g and IL-12p40 in vivo during rejection of aPD-1 treatment-sensitive MC38 tumor cells. Intravital imaging of the tumor microenvironment revealed a 6 fold expansion of IFNγ-eYFP+cells 1 day after a single aPD-1 injection. IL-12p40-eYFP+cells displayed a branched morphology, suggesting that they were DCs. To provide a more comprehensive and unbiased view of immunotherapeutic responses across the tumor immune microenvironment, they performed scRNAseq analysis on CD45+cells isolated from untreated or aPD-1-treated tumors. scRNaseq analysis confirmed the expansion of IL-12+DCs after aPD-1 treatment. Then they used intravital imaging to track IL-12 expression in mice depleted of CD8+T cells prior to administration of aPD-1. Absence of CD8+T cells abrogated IL-12 production. Besides, IFN-g blockade reduced IL-12 production within the tumor microenvironment. Decreased IL-12 production by DCs and decreased numbers of IL-12+DCs both contributed to this reduction. What’s more, tumor-infiltrating T cells can respond to IL-12 and increased IFN-γproduction. These findings suggest that full-fledged activation of antitumor T cells by anti-PD-1 is not direct, but rather involves T cell:DC crosstalk and is licensed by IFN-g and IL-12. doi: 10.1016/j.immuni.2018.09.024 Edited by Biaolong Deng |
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