Annalisa Del PreteValentina SalviAlessandra SorianiMattia Laffranchi...
432-447页
查看更多>>摘要：Dendritic cells(DCs)exhibit a specialized antigen-presenting function and play crucial roles in both innate and adaptive immune responses.Due to their ability to cross-present tumor cell-associated antigens to naïve T cells,DCs are instrumental in the generation of specific T-cell-mediated antitumor effector responses in the control of tumor growth and tumor cell dissemination.Within an immunosuppressive tumor microenvironment,DC antitumor functions can,however,be severely impaired.In this review,we focus on the mechanisms of DC capture and activation by tumor cell antigens and the role of the tumor microenvironment in shaping DC functions,taking advantage of recent studies showing the phenotype acquisition,transcriptional state and functional programs revealed by scRNA-seq analysis.The therapeutic potential of DC-mediated tumor antigen sensing in priming antitumor immunity is also discussed.
Paola FacherisJane JefferyEster Del DucaEmma Guttman-Yassky...
448-474页
查看更多>>摘要：Atopic dermatitis(AD)is the most common inflammatory skin disease,and it is considered a complex and heterogeneous condition.Different phenotypes of AD,defined according to the patient age at onset,race,and ethnic background;disease duration;and other disease characteristics,have been recently described,underlying the need for a personalized treatment approach.Recent advancements in understanding AD pathogenesis resulted in a real translational revolution and led to the exponential expansion of the therapeutic pipeline.The study of biomarkers in clinical studies of emerging treatments is helping clarify the role of each cytokine and immune pathway in AD and will allow addressing the unique immune fingerprints of each AD subset.Personalized medicine will be the ultimate goal of this targeted translational research.In this review,we discuss the changes in the concepts of both the pathogenesis of and treatment approach to AD,highlight the scientific rationale behind each targeted treatment and report the most recent clinical efficacy data.
查看更多>>摘要：The activation of NLRC4 is a major host response against intracellular bacteria infection.However,NLRC4 activation after a host senses diverse stimuli is difficult to understand.Here,we found that the lncRNA LNCGM1082 plays a critical role in the activation of NLRC4.LNCGM1082 in macrophages affects the maturation of interleukin(IL)-1β and pyroptotic cell death only after exposure to an NLRC4 ligand.Similar to NLRC4-/-mice,LNCGM1082-/-mice were highly sensitive to Salmonella Typhimurium(S.T)infection.LNCGM1082 deficiency in mouse or human macrophages inhibited IL-1β maturation and pyroptosis.Mechanistically,LNCGM1082 induced the binding of PKCδ with NLRC4 in both mice and humans.In contrast,NLRC4 did not bind PKCδ in LNCGM1082-/-macrophages.The activity of the lncRNA LNCGM1082 induced by S.T may be mediated through TLR5 in the macrophages of both mice and humans.In summary,our data indicate that TLR5-mediated LNCGM1082 activity can promote the binding of PKCδ with NLRC4 to activate NLRC4 and induce resistance to bacterial infection.
查看更多>>摘要：Chronic antigenic stimulation can trigger the differentiation of antigen-experienced CD4+T cells into T regulatory type 1(TR1)cells,a subset of interleukin-10-producing Treg cells that do not express FOXP3.The identities of the progenitor(s)and transcriptional regulators of this T-cell subset remain unclear.Here,we show that the peptide-major histocompatibility complex class II(pMHCII)monospecific immunoregulatory T-cell pools that arise in vivo in different genetic backgrounds in response to pMHCII-coated nanoparticles(pMHCII-NPs)are invariably comprised of oligoclonal subpools of T follicular helper(TFH)and TR1 cells with a nearly identical clonotypic composition but different functional properties and transcription factor expression profiles.Pseudotime analyses of scRNAseq data and multidimensional mass cytometry revealed progressive downregulation and upregulation of TFH and TR1 markers,respectively.Furthermore,pMHCII-NPs trigger cognate TR1 cell formation in TFH cell-transfused immunodeficient hosts,and T-cell-specific deletion of Bcl6 or Irf4 blunts both the TFH expansion and TR1 formation induced by pMHCII-NPs.In contrast,deletion of Prdm1 selectively abrogates the TFH-to-TR1 conversion.Bcl6 and Prdm1 are also necessary for anti-CD3 mAb-induced TR1 formation.Thus,TFH cells can differentiate into TR1 cells in vivo,and BLIMP1 is a gatekeeper of this cellular reprogramming event.
查看更多>>摘要：CD8+ T cells play a central role in antiviral immune responses.Upon infection,naive CD8+ T cells differentiate into effector cells to eliminate virus-infected cells,and some of these effector cells further differentiate into memory cells to provide long-term protection after infection is resolved.Although extensively investigated,the underlying mechanisms of CD8+ T-cell differentiation remain incompletely understood.Themis is a T-cell-specific protein that plays critical roles in T-cell development.Recent studies using Themis T-cell conditional knockout mice also demonstrated that Themis is required to promote mature CD8+ T-cell homeostasis,cytokine responsiveness,and antibacterial responses.In this study,we used LCMV Armstrong infection as a probe to explore the role of Themis in viral infection.We found that preexisting CD8+ T-cell homeostasis defects and cytokine hyporesponsiveness do not impair viral clearance in Themis T-cell conditional knockout mice.Further analyses showed that in the primary immune response,Themis deficiency promoted the differentiation of CD8+ effector cells and increased their TNF and IFNγ production.Moreover,Themis deficiency impaired memory precursor cell(MPEC)differentiation but promoted short-lived effector cell(SLEC)differentiation.Themis deficiency also enhanced effector cytokine production in memory CD8+ T cells while impairing central memory CD8+ T-cell formation.Mechanistically,we found that Themis mediates PD-1 expression and its signaling in effector CD8+ T cells,which explains the elevated cytokine production in these cells when Themis is disrupted.
查看更多>>摘要：CD4+ T cells play major roles in the adaptive immune system,which requires antigen recognition,costimulation,and cytokines for its elaborate orchestration.Recent studies have provided new insight into the importance of the supramolecular activation cluster(SMAC),which comprises concentric circles and is involved in the amplification of CD4+ T cell activation.However,the underlying mechanism of SMAC formation remains poorly understood.Here,we performed single-cell RNA sequencing of CD4+ T cells left unstimulated and stimulated with anti-CD3 and anti-CD28 antibodies to identify novel proteins involved in their regulation.We found that intraflagellar transport 20(IFT20),previously known as cilia-forming protein,was upregulated in antibody-stimulated CD4+ T cells compared to unstimulated CD4+ T cells.We also found that IFT20 interacted with tumor susceptibility gene 101(TSG101),a protein that endocytoses ubiquitinated T-cell receptors.The interaction between IFT20 and TSG101 promoted SMAC formation,which led to amplification of AKT-mTOR signaling.However,IFT20-deficient CD4+ T cells showed SMAC malformation,resulting in reduced CD4+ T cell proliferation,aerobic glycolysis,and cellular respiration.Finally,mice with T-cell-specific IFT20 deficiency exhibited reduced allergen-induced airway inflammation.Thus,our data suggest that the IFT20-TSG101 axis regulates AKT-mTOR signaling via SMAC formation.
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