Journal of Experimental Medicine最新文献

Amino acids are essential for the activation and function of CD4 T helper (Th) cells, which differentiate into Th1, Th2, Th17, and Treg subsets to coordinate immune responses. While specific amino acid transporters have been identified for Th1, Th17, and Tregs, a transporter regulating Th2 cells remains unknown. This study identifies SLC7A8 as a Th2-specific amino acid transporter in the Th compartment. We found that Slc7a8 expression is upregulated in Th2 cells compared with other T helper subsets, and Slc7a8 deficiency impairs Th2 cell proliferation and cytokine production. Furthermore, SLC7A8 was found to be crucial for an effective type 2 immune response to helminth infection and allergen-induced lung inflammation. Mechanistically, Slc7a8 deficiency disrupted Th2 cell metabolism, leading to reduced mTOR activation and, consequently, diminished mitochondrial function along with an impaired c-Myc pathway; these defects cumulatively induced cellular stress that curtailed cell growth and survival. Collectively, these findings highlight a previously unknown role for SLC7A8 in Th2 cells, with potential implications for understanding and treating type 2 immune-related diseases.

MHC class I-related protein (MR1) presents vitamin B-based antigens (Ags) to mucosal-associated invariant T (MAIT) cells. While microbial riboflavin (RF) precursors are well-documented MR1 ligands, it is unclear whether host-generated RF catabolites influence MR1 immunity. Here, we report that RF catabolites, including 10-formylmethylflavin (FMF), lumichrome, lumiflavin, and alloxazine, bind to MR1 with moderate affinity, while RF itself binds weakly. In contrast to the MR1-upregulating microbial RF precursors, RF catabolites reduced the surface level of MR1 by inducing its retention in the endoplasmic reticulum and inhibiting exit. These RF catabolites weakly competed with vitamin B-based Ags for MR1 binding, thereby selectively inhibiting MAIT activation. The crystal structures of MR1 with RF, FMF, lumiflavin, and lumichrome show binding in the A'-pocket of MR1. Here, lumichrome formed a "flavin bond" covalent interaction with MR1-Lys43 differing from the typical Schiff base. Collectively, we identified three-ringed isoalloxazines that bind MR1 and reduce surface levels, suggesting a potential role in dampening MAIT cell immunity.

Variants of uncertain significance (VUS) are a major obstacle in genetic diagnosis, particularly when involving gain-of-function (GoF) mutations that are poorly predicted in silico. MEFV, which encodes the inflammasome sensor pyrin, is mutated in two autoinflammatory diseases, familial Mediterranean fever (FMF) and pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). Here, we developed SpeckSeq, a method that combines DNA bar-coding, ASC speck-based single-cell sorting and next-generation sequencing to systematically identify hypermorphic MEFV variants in response to different stimuli. SpeckSeq identified 49 GoF mutations separated into two distinct groups containing either PAAND variants or FMF variants. SpeckSeq was validated using patients' cells and supported a reclassification of MEFV variant pathogenicity, leading to novel diagnoses. As a large-scale mutagenesis approach, using human genetics as a guide, SpeckSeq revealed structural and functional pyrin features, including a putative ligand-accommodating cavity in the B30.2 domain. Altogether, SpeckSeq classifies VUS to refine molecular diagnostics and improve our knowledge on the pyrin inflammasome.

Insights into HIV-1 pathogenesis have come from studies of viral dynamics. However, there is little information on viral dynamics in lentiviral infections in which viral replication is naturally controlled in a subset of infected individuals. We evaluated the decay of simian immunodeficiency virus (SIV) RNA and cell-associated SIV genomes in a nonhuman primate (NHP) model in which replication of an engineered SIV variant is naturally controlled by cellular immune responses in most infected animals. This variant lacks a trafficking motif in the gp41 cytoplasmic tail. A trajectory of control was evident by 21 days after infection. In animals with natural control, we observed similar biphasic decay of intact proviruses in blood and lymph nodes, at rates close to those in animals that failed to control the virus and were put on antiretroviral therapy (ART). Both natural control and ART effectively blocked viral evolution, but not persistence. Thus, in this NHP model, natural control can be nearly as effective as ART in controlling viral replication.

T cell engagers (TCEs) are antibody-based constructs designed to transiently reprogram cytotoxic T lymphocytes for target cell elimination by simultaneously binding the T cell receptor and a specific surface antigen on the target cell. Over the past 12 years, 10 TCEs were approved by the US Food and Drug Administration, and an additional two by the European Medicines Agency. Nine TCEs treat hematologic malignancies, and three target solid tumors. Over 150 TCEs are being investigated in clinical trials, recently also in autoimmune diseases. Here, we discuss the learnings from the 12 approved TCEs. A surprising variety of molecular designs and biochemical characteristics appear suitable for approval. On the clinical side, we review targets, indications, dosing, schedules, side effects, mitigation strategies for adverse events, and efficacy. High flexibility in design and choice of target, scalability, high response rates as a monotherapy in hematologic malignancies, and emerging efficacy against solid tumors and in autoimmune diseases make TCEs an attractive therapeutic modality.

Resident memory CD8+ T cells (Trms) are essential for protecting barrier nonlymphoid tissues (NLTs) against reinfection, yet the involvement of dendritic cells (DCs) in this process and the nature of Trm-DC interactions within these tissues remain poorly understood. Our study demonstrates that upon reactivation, memory CD8+ T cells located in the skin-independently of circulating memory counterparts-initiate the infiltration and maturation of plasmacytoid DCs (pDCs) in the tissue. This, in turn, promotes the maturation of conventional type 1 DCs (cDC1s) through type I IFN (IFN-I) signaling in a pDC-dependent manner. Depletion of pDCs or blocking IFN-I signaling disrupts this axis, severely impairing Trm-driven protection against secondary infections with vaccinia virus (VACV) in the skin. Notably, this pDC-dependent, IFN-I-mediated pathway is also essential for Trm-mediated protection against secondary respiratory infections with influenza A virus (IAV). Our findings uncover a crucial collaboration between Trm, pDCs, and cDC1s, offering new insights for enhancing vaccines.

Respiratory viral infections establish tissue-resident memory T cells (TRM) in the lung, which provide optimal protection against subsequent infections, though the underlying mechanisms are incompletely understood. Here, we demonstrate in a mouse model of heterosubtypic influenza infection that lung TRM attenuate inflammation by macrophages during secondary versus primary responses, in part, through production of the immunoregulatory cytokine IL-10. During secondary infections, lung TRM were the predominant producers of early IL-10; inhibiting early IL-10 signaling resulted in increased macrophage-mediated inflammation, morbidity, and lung pathology. Moreover, lung TRM were shown to directly modulate lung macrophage responses and polarization in depletion experiments. Finally, IL-10 enhanced IFN-γ production by lung memory CD8+ T cells. Human influenza-specific TRM isolated from lungs recapitulated robust IL-10 expression associated with augmented effector responses of murine TRM. These data support a dual role of TRM in coordinating in situ secondary responses-augmenting effector responses for robust viral clearance while dampening inflammation to limit tissue damage.

Genetic variants in the FCRL3 gene are linked to autoimmune disorders. However, the functional properties of FCRL3-expressing T lymphocytes, and the regulation and functional impact of FCRL3 expression remain understudied. Here, we performed a multiomic and functional analysis of human T lymphocytes expressing FCRL3. FCRL3 expression correlated with reduced capacity of T cells to undergo activation and was accompanied by functional specialization toward a cytotoxic phenotype, resembling cytotoxic CD4+ T lymphocytes and CD8+ effector memory TEMRA cells. FCRL3 expression was induced upon repetitive TCR engagement, and sufficed to attenuate T cell responses, indicating a role as a negative regulator of the activation of differentiated T cell subsets with high cytotoxic capacity. Mechanistically, the cytoplasmic domain of FCRL3 engaged inhibitory molecules, suggesting a direct role in limiting activating signals. Overall, our study establishes FCRL3 as a functional immunoregulatory receptor that restrains the activation of highly specialized human memory T cells.

Polyglutamine (polyQ) diseases, caused by a CAG repeat expansion encoding a glutamine tract in nine distinct proteins, present a complex molecular puzzle in which each piece contributes to neurodegeneration. While each of the causative proteins has a distinct function, the downstream consequences of polyQ toxicity are often similar, including protein accumulation, transcriptional dysregulation, somatic CAG repeat instability, disrupted energy homeostasis, compromised synaptic function, and selective neuronal death. This review summarizes emerging insights into how proteins with an expanded polyQ tract disrupt distinct cellular functions, and we examine a multitude of discoveries that are inspiring and reshaping novel therapeutic strategies.