
Monoclonal antibodies derived from PcrV-specific B cells of cystic fibrosis patients exhibit potent anti-Pseudomonas aeruginosa activity in a mouse pneumonia model.


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Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease in a variety of animal models. However, clinical trials of PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations of antibodies identified using protein-immunized animal systems and required extensive engineering to optimize binding and/or reduce immunogenicity. Of note, PA infections are common in people with cystic fibrosis (pwCF), who are generally believed to mount normal adaptive immune responses. Here we utilized a tetramer reagent to detect and isolate PcrV-specific B cells in pwCF and, via single-cell sorting and paired-chain sequencing, identified the B cell receptor (BCR) variable region sequences that confer PcrV-specificity. We derived multiple high affinity anti-PcrV monoclonal antibodies (mAbs) from PcrV-specific B cells across 3 donors, including mAbs that exhibit potent anti-PA activity in a murine pneumonia model. This robust strategy for mAb discovery expands what is known about PA-specific B cells in pwCF and yields novel mAbs with potential for future clinical use.

### Competing Interest Statement

The authors have declared no competing interest.

Monoclonal antibodies derived from B cells in subjects with cystic fibrosis reduce Pseudomonas aeruginosa burden in mice

protective-monoclonal-antibodies-against-pseudomonas-aeruginosa-derived-from-b-cells-of-cystic-fibrosis-patients


Protective Monoclonal Antibodies Against Pseudomonas aeruginosa Derived from B Cells of Cystic Fibrosis Patients


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Expression of a single inhibitory Ly49 receptor is sufficient to license natural killer cells and enable their efficient rejection of MHC-I deficient target cells.


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

a-single-inhibitory-ly49-receptor-is-sufficient-to-license-natural-killer-cells-and-mediate-missing-self-recognition


A Single Inhibitory Ly49 Receptor Is Sufficient to License Natural Killer Cells and Mediate Missing-Self Recognition



Neutrophils (Ly6G+ granulocytes) serve as a major niche for Mycobacterium tuberculosis (Mtb) in the lungs, and their IL-17 production establishes a pro-pathogenic axis that exacerbates tuberculosis disease.


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

neutrophils-serve-as-a-permissive-niche-for-mycobacterium-tuberculosis-promoting-disease-pathogenesis-through-an-il-17-dependent-mechanism


Neutrophils Serve as a Permissive Niche for Mycobacterium tuberculosis, Promoting Disease Pathogenesis through an IL-17-Dependent Mechanism



Ctla-4 deficiency leads to intestinal inflammation, epithelial barrier disruption, altered immune cell composition, and dysbiosis in the zebrafish intestine, closely resembling the pathological features of inflammatory bowel disease.


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

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Zebrafish Model Reveals Crucial Role of Ctla-4 in Maintaining Intestinal Immune Homeostasis and Preventing Inflammatory Bowel Disease



Type 2 cytokine Fc-IL-4 can directly act on CD8+ T cells to enrich and reinvigorate terminally exhausted CD8+ T cells, thereby enhancing the efficacy of type 1 immunity-based cancer immunotherapies.


Fc–IL-4, a typical type 2 cytokine, reinvigorates exhausted CD8+ T cells in tumours, underscoring this fusion protein as a potent immunotherapy that synergizes effectively with type 1 immunity against cancer.

The type 2 cytokine Fc–IL-4 revitalizes exhausted CD8+ T cells against cancer - Nature

harnessing-type-2-immunity-to-revitalize-exhausted-cd8-t-cells-and-enhance-cancer-immunotherapy


Harnessing Type 2 Immunity to Revitalize Exhausted CD8+ T Cells and Enhance Cancer Immunotherapy



アレルゲンに対する感覚神経の反応性は、γδT細胞が産生するIL-3によって制御されている。


A γδ T cell–IL-3 signalling axis is defined that controls the allergen responsiveness of cutaneous sensory neurons, leading to evidence for an immune rheostat that governs sensory neuronal responses to allergens on first exposure.

A γδ T cell–IL-3 axis controls allergic responses through sensory neurons - Nature

アレルギー反応を感覚神経を介して制御するγδt細胞-il-3経路


アレルギー反応を感覚神経を介して制御するγδT細胞-IL-3経路



A γδ T cell-derived cytokine, IL-3, acts on sensory neurons to lower their activation threshold to allergens, thereby promoting the initiation of allergic immune responses.


uncovering-the-immune-neuronal-axis-controlling-allergic-responses-a-γδ-t-cell-il-3-signaling-pathway-regulates-sensory-neuron-activation-by-allergens


Uncovering the Immune-Neuronal Axis Controlling Allergic Responses: A γδ T Cell–IL-3 Signaling Pathway Regulates Sensory Neuron Activation by Allergens



Humans can fight infections effectively even without the immune signaling protein TNF.


Insights about the immune system of people who lack a defence protein.

People who lack the immune protein TNF can still fight infection

surprising-insights-into-the-role-of-tnf-in-human-immune-response-to-infections


Surprising Insights into the Role of TNF in Human Immune Response to Infections



CD8 CAR T 세포에서 비대칭 세포 분열은 세포 표면 단백질과 전사체의 비대칭적 분배를 유발하여 서로 다른 운명을 결정한다.


We show that target-induced proximity labelling enables isolation of first-division CD8 chimeric antigen receptor T cells that asymmetrically distribute their surface proteome and transcriptome, resulting in distinct phenotypic, metabolic&nbsp;and functional profiles&nbsp;in proximal and distal&nbsp;daughter cells.

Fate induction in CD8 CAR T cells through asymmetric cell division - Nature

cd8-car-t-세포에서-비대칭-세포-분열을-통한-운명-유도


CD8 CAR T 세포에서 비대칭 세포 분열을 통한 운명 유도



IRE1α, a key regulator of the unfolded protein response, is activated in macrophages during Candida albicans infection through a non-canonical, protein misfolding-independent mechanism involving C-type lectin receptor signaling. IRE1α activity supports phagosome maturation and calcium flux, enabling macrophages to effectively kill phagocytosed C. albicans.


While the canonical function of IRE1α is to detect misfolded proteins and activate the unfolded protein response (UPR) to maintain cellular homeostasis, microbial pathogens can also activate IRE1α, which modulates innate immunity and infection outcomes. However, how infection activates IRE1α and its associated inflammatory functions have not been fully elucidated. Recognition of microbe-associated molecular patterns can activate IRE1α, but it is unclear whether this depends on protein misfolding. Here, we report that a common and deadly fungal pathogen, Candida albicans , activates macrophage IRE1α through C-type lectin receptor signaling, reinforcing a role for IRE1α as a central regulator of host responses to infection by a broad range of pathogens. This activation did not depend on protein misfolding in response to C. albicans infection. Moreover, lipopolysaccharide treatment was also able to activate IRE1α prior to protein misfolding, suggesting that pathogen-mediated activation of IRE1α occurs through non-canonical mechanisms. During C. albicans infection, we observed that IRE1α activity promotes phagolysosomal fusion that supports the fungicidal activity of macrophages. Consequently, macrophages lacking IRE1α activity displayed inefficient phagosome maturation, enabling C. albicans to lyse the phagosome, evade fungal killing, and drive aberrant inflammatory cytokine production. Mechanistically, we show that IRE1α activity supports phagosomal calcium flux after phagocytosis of C. albicans , which is crucial for phagosome maturation. Importantly, deletion of IRE1α activity decreased the fungicidal activity of phagocytes in vivo during systemic C. albicans infection. Together, these data provide mechanistic insight for the non-canonical activation of IRE1α during infection, and reveal central roles for IRE1α in macrophage antifungal responses.

### Competing Interest Statement

The authors have declared no competing interest.

Non-canonical activation of IRE1α during Candida albicans infection enhances macrophage fungicidal activity

non-canonical-activation-of-ire1α-promotes-macrophage-antifungal-responses-during-candida-albicans-infection


Non-canonical Activation of IRE1α Promotes Macrophage Antifungal Responses During Candida albicans Infection
