
EPCR 결합을 억제하는 광범위 반응성 인간 단일 클론 항체를 통해 중증 말라리아에 대한 새로운 백신 및 치료법 개발 가능성 제시


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Two broadly reactive and inhibitory human monoclonal antibodies against the malaria parasite Plasmodium falciparum have been characterized, providing insights into immunity, prevention and&nbsp;treatment of severe malaria.

Broadly inhibitory antibodies to severe malaria virulence proteins - Nature

중증-말라리아-독성-단백질에-대한-광범위-억제-항체-발견


중증 말라리아 독성 단백질에 대한 광범위 억제 항체 발견


title_rewrite


SARS-CoV-2의 새로운 변이체인 JN.1 lineage, 특히 KP.2 및 KP.3 하위 변이체는 기존 XBB lineage에 비해 높은 면역 회피력을 보이며, JN.1 감염 또는 백신 접종으로 유도된 항체 반응 역시 KP.2/KP.3에 대해서는 효과가 제한적이므로, 이러한 변이체를 표적으로 하는 업데이트된 부스터 백신 개발이 시급하다.


Evolving antibody response to SARS-CoV-2 antigenic shift from XBB to JN.1 - Nature

xbb에서-jn-1으로의-sars-cov-2-항원-변이에-대한-진화하는-항체-반응-kp-2-kp-3-기반-부스터-백신의-필요성-강조


XBB에서 JN.1으로의 SARS-CoV-2 항원 변이에 대한 진화하는 항체 반응: KP.2/KP.3 기반 부스터 백신의 필요성 강조



신경펩타이드 CGRP는 바이러스 감염 시 뉴런에서 생성되어 T 세포 수용체 RAMP3에 작용하여 TH1 세포 분화를 촉진하고 항바이러스 면역 반응을 강화한다.


RAMP3, a component of the receptor for the neuropeptide CGRP, has a cell-intrinsic role in T helper type 1 cell fate determination.

Neuropeptide signalling orchestrates T cell differentiation - Nature

신경펩타이드-신호전달-t-세포-분화-조절에-중요한-역할


신경펩타이드 신호전달, T 세포 분화 조절에 중요한 역할



면역 체크포인트 분자인 PD-1의 자극은 Th2 세포로의 분화를 선택적으로 억제하여 알레르기 염증 반응을 조절하는 데 중요한 역할을 한다.


Programmed Cell Death Protein-1 (PD-1) represents endogenous mechanisms of negative immunoregulation. While the modulation of effector functions has been the major focus of PD-1 research, quick PD-1 upregulation in naïve T cells starting 1 h after priming raised a possibility that PD-1 also affects the development of effector T cells. The role of PD-1 in functional differentiation into Th1 and Th2 has been unclear. In murine naïve CD4+ T cell activation, we found that PD-1 stimulation during the early stage of T cell activation strongly impaired Th2 cell development, while Th1 cell induction was relatively resistant to this immunosuppressive signaling. The steep decline in Th2 cell induction suggested the significance of PD-1 in allergic inflammation. Treatment with anti-human PD-1 agonist antibody inhibited allergic inflammation in human PD-1-knock-in mice as shown by the reduction of Th2 cells, IgE levels and eosinophilic infiltration. This study shows that PD-1 regulates not only the intensity but also the quality of immune response by deviating Th differentiation. PD-1 stimulators are projected to be valuable in suppressing various forms of inflammatory activities, but the efficacy against Th2-dominant immune response may be particularly high.

### Competing Interest Statement

M.T., K.S., Y.T., T.H. and A.O. are inventors on patent applications (WO2021/241523A1, WO2022/239820) submitted by Foundation for Biomedical Research and Innovation at Kobe, National Institutes of Biomedical Innovation, Health and Nutrition, and Meiji Seika Pharma Co. Ltd. that cover anti-human PD-1 agonist antibodies and their therapeutic application. K.S. and Y.T. are employees of Meiji Seika Pharma Co. Ltd. The remaining authors declare no competing interests.

PD-1 negatively regulates helper T cell differentiation into Th2

pd-1-th2-세포로의-보조-t-세포-분화를-부정적으로-조절한다


PD-1, Th2 세포로의 보조 T 세포 분화를 부정적으로 조절한다



BCG 백신 접종 후 비장 내에서 STAT1 신호 전달 경로를 통한 초기 면역 반응이 장기적인 훈련 면역 형성에 중요한 역할을 한다.


Trained immunity (TI) is the process wherein innate immune cells gain functional memory upon exposure to specific ligands or pathogens, leading to augmented inflammatory responses and pathogen clearance upon secondary exposure. While the differentiation of hematopoietic stem cells (HSCs) and reprogramming of bone marrow (BM) progenitors are well-established mechanisms underpinning durable TI protection, remodeling of the cellular architecture within the tissue during TI remains underexplored. Here, we study the effects of peritoneal Bacillus Calmette–Guérin (BCG) administration to find TI-mediated protection in the spleen against a subsequent heterologous infection by the Gram-negative pathogen Salmonella Typhimurium ( S .Tm). Utilizing single cell RNA-sequencing and flow cytometry, we discerned STAT1-regulated genes in TI-associated resident and recruited splenic myeloid populations. The temporal dynamics of TI were further elucidated, revealing both early and delayed myeloid subsets with time-dependent, cell type-specific STAT1 signatures. Using lineage tracing, we find that tissue-resident red pulp macrophages (RPM), initially depleted by BCG exposure, are restored from both tissue-trained, self-renewing macrophages and from bone marrow-derived progenitors, fostering long lasting local defense. Early inhibition of STAT1 activation, using specific JAK-STAT inhibitors, reduces both RPM loss and recruitment of trained monocytes. Our study suggests a temporal window soon after BCG vaccination, in which STAT1-dependent activation of long-lived resident cells in the tissue mediates localized protection.

### Competing Interest Statement

The authors have declared no competing interest.

Early and Delayed STAT1-Dependent Responses Drive Local Trained Immunity of Macrophages in the Spleen

비장-대식세포의-국소-훈련-면역에서-stat1-의존적-반응의-초기-및-지연된-역할


비장 대식세포의 국소 훈련 면역에서 STAT1 의존적 반응의 초기 및 지연된 역할



아르기닌 대사 조절을 통해 면역 억제적 M2형 종양 관련 대식세포를 면역 활성화 M1형으로 재프로그래밍하여 HER2 양성 유방암의 면역 반응을 증진시킬 수 있다.


HER2+ breast tumors have abundant immune-suppressive cells, including M2-type tumor associated macrophages (TAMs). While TAMs consist of the immune-stimulatory M1-type and immune-suppressive M2-type, M1/M2-TAM ratio is reduced in immune-suppressive tumors, contributing to their immunotherapy refractoriness. M1 vs. M2-TAM formation depends on differential arginine metabolism, where M1-TAMs convert arginine to nitric oxide (NO) and M2- TAMs convert arginine to polyamines (PAs). We hypothesize that such distinct arginine metabolism in M1- vs M2-TAMs is attributed to different availability of BH4 (NO synthase cofactor) and that its replenishment would reprogram M2-TAMs to M1-TAMs. Recently, we reported that sepiapterin (SEP), the endogenous BH4 precursor, elevates the expression of M1- TAM markers within HER2+ tumors. Here, we show that SEP restores BH4 levels in M2-TAMs, which then redirects arginine metabolism to NO synthesis and converts M2-TAMs to M1-TAMs. The reprogrammed TAMs exhibit full-fledged capabilities of antigen presentation and induction of effector T cells to trigger immunogenic cell death of HER2+ cancer cells. This study substantiates the utility of SEP in metabolic shift of HER2+ breast tumor microenvironment as a novel immunotherapeutic strategy.

Reprogramming of breast tumor-associated macrophages with modulation of arginine metabolism

her2-양성-유방암에서-아르기닌-대사-조절을-통한-종양-관련-대식세포의-재프로그래밍


HER2 양성 유방암에서 아르기닌 대사 조절을 통한 종양 관련 대식세포의 재프로그래밍



초파리의 기생벌에 대한 체액성 면역 반응은 JAK/STAT, NF-κB 및 GATA 신호 경로에 의해 조절된다.


The two arms of innate immunity consist of the cell-mediated cellular defenses and the systemic humoral immune responses. Drosophila humoral immune defenses in the context of antimicrobial immunity, particularly the regulation and activation of antimicrobial peptide secretion from the fat body, have been studied extensively. How Drosophila regulates humoral immunity against another major natural enemy, the parasitoid wasp, is less well-characterized. In this study, we focused on a gene crucial in anti-parasitoid immunity, lectin-24A , which is specifically induced following parasitization. We found that a fluorescent reporter driven by the region upstream of lectin-24A showed localized posterior expression in the larval fat body, the Drosophila tissue mediating humoral immunity. Furthermore, with RNA sequencing of the anterior and posterior fat body sections, we found that components of JAK/STAT, GATA, and Toll pathways were regulated differentially in the anterior-posterior axis of the fat body and/or by infection. Predicted binding motifs for transcription factors in all three of these pathways were identified in the 444bp upstream region of the lectin-24A gene, where scrambling these motifs leads to reduced basal or induced expression of the fluorescent reporter. Investigating each of these pathways, we found that JAK/STAT, the GATA factor Pannier, and the NF-κB factor dorsal all modulate the expression of lectin-24A . The binding motifs associated with these transcription factors were also enriched in the upstream sequences of parasitism-induced genes in the fat body. Taken together, these results indicate that JAK/STAT, Pannier, and NF-κB signaling are involved in the regulation of lectin-24A and, more generally, Drosophila humoral anti-parasitoid immunity after infection.

### Competing Interest Statement

The authors have declared no competing interest.

A humoral immune response to parasitoid wasps in Drosophila is regulated by JAK/STAT, NF-κB and GATA

기생벌에-대한-초파리의-체액성-면역-반응은-jak-stat-nf-κb-및-gata에-의해-조절됨


기생벌에 대한 초파리의 체액성 면역 반응은 JAK/STAT, NF-κB 및 GATA에 의해 조절됨



단일 억제성 Ly49 수용체 발현만으로도 NK 세포의 면허화와 자기 MHC-I 결핍 세포 제거가 가능하다.


Natural killer (NK) cells recognize target cells through germline-encoded activation and inhibitory receptors enabling effective immunity against viruses and cancer. The Ly49 receptor family in the mouse and killer immunoglobin-like receptor family in humans play a central role in NK cell immunity through recognition of MHC class I and related molecules. Functionally, these receptor families are involved in licensing and rejection of MHC-I-deficient cells through missing-self. The Ly49 family is highly polymorphic, making it challenging to detail the contributions of individual Ly49 receptors to NK cell function. Herein, we showed mice lacking expression of all Ly49s were unable to reject missing-self target cells in vivo , were defective in NK cell licensing, and displayed lower KLRG1 on the surface of NK cells. Expression of Ly49A alone on a H-2Dd background restored missing-self target cell rejection, NK cell licensing, and NK cell KLRG1 expression. Thus, a single inhibitory Ly49 receptor is sufficient to license NK cells and mediate missing-self in vivo .

### Competing Interest Statement

The authors have declared no competing interest.

Expression of a single inhibitory Ly49 receptor is sufficient to license NK cells for effector functions

단일-억제성-ly49-수용체-발현만으로도-nk-세포의-효과기-기능-활성화에-충분하다


단일 억제성 Ly49 수용체 발현만으로도 NK 세포의 효과기 기능 활성화에 충분하다



결핵 감염 시 호중구(Ly6G+ 세포)가 주요 IL-17 생산원이며, IL-17-COX2-호중구 축이 결핵 병원성을 악화시킨다.


The protective correlates of Mycobacterium tuberculosis ( Mtb ) infection-elicited host immune responses are incompletely understood. Here, we report pro-pathogenic crosstalk involving Ly6G+granulocytes (Ly6G+Gra), IL-17 and COX2. We show that in the lungs of Mtb -infected wildtype mice, either BCG-vaccinated or not, most intracellular bacilli are Ly6G+Gra-resident four weeks post-infection onwards. In the genetically susceptible IFNγ−/− mice, excessive Ly6G+Gra infiltration correlates with severe bacteraemia. Neutralizing IL-17 (anti-IL17mAb) and COX2 inhibition by celecoxib reverse Ly6G+Gra infiltration, associated pathology and death in IFNγ−/− mice. Surprisingly, Ly6G+Gra also serves as the major source of IL-17 in the lungs of Mtb -infected WT or IFNγ−/− mice. The IL-17-COX2-Ly6G+Gra interplay also operates in WT mice. Inhibiting RORγt, the key transcription factor for IL-17 production or COX2, reduces the bacterial burden in Ly6G+Gra, leading to reduced bacterial burden and pathology in the lungs of WT mice. In the Mtb -infected WT mice, COX2 inhibition abrogates IL-17 levels in the lung homogenates and significantly enhances BCG’s protective efficacy, mainly by targeting the Ly6G+Gra-resident Mtb pool. Furthermore, in pulmonary TB patients, high neutrophil count and IL-17 correlated with adverse treatment outcomes. Together, our results suggest that IL-17 and PGE2 are the negative correlates of protection, and we propose targeting the pro-pathogenic IL-17-COX2-Ly6G+Gra axis for TB prevention and therapy.

### Competing Interest Statement

The authors have declared no competing interest.

Ly6G+Granulocytes-derived IL-17 limits protective host responses and promotes tuberculosis pathogenesis

결핵-병원성에-기여하는-호중구-유래-il-17


결핵 병원성에 기여하는 호중구 유래 IL-17



Ctla-4 결핍은 제브라피시에서 염증성 장 질환과 유사한 표현형을 유발하며, 이는 Ctla-4가 장내 면역 항상성 유지에 필수적인 역할을 한다는 것을 보여줌.


Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disorder characterized by intestinal inflammation and epithelial injury. The underlying causes of IBD are not fully understood, but genetic factors have implicated in genome-wide association studies, including CTLA-4, an essential negative regulator of T cell activation. However, establishing a direct link between CTLA-4 and IBD has been challenging due to the early lethality of CTLA-4 knockout mice. In this study, we identified zebrafish Ctla-4 homolog and investigated its role in maintaining intestinal immune homeostasis by generating a Ctla-4-deficient ( ctla-4-/- ) zebrafish line. These mutant zebrafish exhibit reduced weight, along with impaired epithelial barrier integrity and lymphocytic infiltration in their intestines. Transcriptomics analysis revealed upregulation of inflammation-related genes, disturbing immune system homeostasis. Moreover, single-cell RNA-sequencing analysis indicated increased Th2 cells and interleukin 13 expression, along with decreased innate lymphoid cells and upregulated proinflammatory cytokines. Additionally, Ctla-4-deficient zebrafish exhibited reduced diversity and an altered composition of the intestinal microbiota. All these phenotypes closely resemble those found in mammalian IBD. Lastly, supplementation with Ctla-4-Ig successfully alleviated intestinal inflammation in these mutants. Altogether, our findings demonstrate the pivotal role of Ctla-4 in maintaining intestinal homeostasis. Additionally, they offer substantial evidence linking CTLA-4 to IBD and establish a novel zebrafish model for investigating both the pathogenesis and potential treatments.

### Competing Interest Statement

The authors have declared no competing interest.

All data generated or analyzed during this study are included in this article and its supplementary information files. The RNA-seq and scRNA-seq data for this study have been deposited in NCBI Gene Expression Omnibus (GEO) (<https://www.ncbi.nlm.nih.gov/geo/>) under accession numbers GSE255304 and GSE255303, respectively. The 16S rRNA sequencing data in this study have been deposited in the NCBI Sequence Read Archive (SRA) (<https://www.ncbi.nlm.nih.gov/sra/>) with an accession number of BioProject PRJNA1073727.

Unraveling the Role of Ctla-4 in Intestinal Immune Homeostasis: Insights from a novel Zebrafish Model of Inflammatory Bowel Disease

장내-면역-항상성-유지에서-ctla-4의-역할-규명-염증성-장-질환-제브라피시-모델로부터의-통찰


장내 면역 항상성 유지에서 Ctla-4의 역할 규명: 염증성 장 질환 제브라피시 모델로부터의 통찰
