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Butyrophilin (BTN) proteins are a type of membrane protein that belongs to the Ig superfamily. They exhibit a high degree of structural similarity to molecules in the B7 family. They fulfill a complex function in regulating immune responses, including immunomodulatory roles, as they influence γδ T cells. The biology of BTN molecules indicates that they are capable of inhibiting the immune system's ability to detect antigens within tumors. A dynamic association between BTN molecules and cellular surfaces is also recognized in specific contexts, influencing their biology. Notably, the dynamism of BTN3A1 is associated with the immunosuppression of T cells or the activation of Vγ9Vδ2 T cells. Cancer immunotherapy relies heavily on T cells to modulate immune function within the intricate interaction of the tumor microenvironment (TME). A significant interaction between the TME and antitumor immunity involves the presence of BTN, which should be taken into account when developing immunotherapy. This review explores potential therapeutic applications of BTN molecules, based on the current understanding of their biology. Significance Statement: Butyrophilin (BTN) molecules have gained significant attention in the realm of cancer treatment due to their emerging roles in the regulation of immune responses. BTN proteins are members of the immunoglobulin superfamily and are expressed on the surface of various cells, including immune cells. The significance of BTN molecules in cancer treatment lies in their ability to modulate immune responses and enhance antitumor immunity, making them potential targets for novel immunotherapy approaches that aim to improve cancer patient outcomes. [ABSTRACT FROM AUTHOR]

Myelin oligodendrocyte glycoprotein (MOG)-IgG-associated disease (MOGAD) is a relatively uncommon autoantibody demyelinating disorder of the central nervous system (CNS) with heterogeneous clinical manifestations and magnetic resonance imaging (MRI) findings. In recent years, a rare MOGAD subtype characterized by distinct clinical and MRI findings has been described. Seizures and cortical hyperintensities best seen on MRI T2-weighted fluid-attenuated inversion recovery (FLAIR) sequences, associated with headache and cerebral spine fluid (CSF) pleocytosis, are the most important characteristics of this MOGAD entity that is named FLAMES (FLAIR hyperintense cortical lesions in MOG-associated encephalitis with seizures). Because of its rarity and the peculiarities of the brain damage and clinical manifestations, it can be under-recognized and confused with focal viral encephalitis, meningitis, subarachnoid hemorrhage, CNS vasculitis, or mitochondrial cytopathy. We described the case of a 4-year-old previously healthy girl who was admitted for focal-onset, tonic-clonic seizures, fever, and headache, combined with optic neuritis. MRI was characterized by FLAIR imaging showing hyperintense cortical lesions, and a mild leukocytosis in the CSF was detected. Efficacy and rapid response to steroid therapy was observed, and no recurrences of neurological problems or further seizures were reported in the following 12 months. This case report can help in understanding FLAMES characteristics in pediatrics in order to favor early diagnosis and prompt therapy. [ABSTRACT FROM AUTHOR]

【Objective】Butyrophilin 1A1 (BTN1A1) gene from Symphysodon aequifasciatus was cloned and its express pattern under pathological infection was analyzed, to provide basis for better understanding of the function of BTN1A1 gene in S. aequifasciatu.【Method】The structure and evolutionary characteristics of two BTN1A1 genes (BTN1A1-1 and BTN1A1-2) were analyzed by bioinformatics analysis. Based on the transcriptome data of the skin of the S. aequifasciatu obtained at early stage, the CDS regions of BTN1A1-1 and BTN1A1-2 genes were used to design the primers for gene cloning. The expressions of BTN1A1-1 gene in various tissues and its expression pattern under the stimulus of Aeromonas hydrophila were analyzed by qRT-PCR.【Result】The ORF regions of BTN1A1-1 and BTN1A1-2 were 894 and 1 275 bp, encoding 298 and 424 amino acids, respectively. Both BTN1A1-1 and BTN1A1-2 had a classical structure of BTN, which contained a signal peptide, an Ig domain, an lg_like domain and a transmembrane domain. BTN1A1-2 also had a cytoplasmic domain. BTN1A1-1 showed a closer relationship with the genes found in cichlid fish. It shared the highest homology of 94.14% with the corresponding amino acid sequences of Archocentrus centrarchus; while BTN1A1-2 showed lower similarity with other types of fish, forming a special branch. The expressions of BTN1A1-1 and BTN1A1-2 were highly in gill, intestine and skin of S. aequifasciatu. The expression of BTN1A1-1 decreased significantly and then increased after the infection of A. hydrophila, while the expression of BTN1A1-2 increased significantly and then decreased.【Conclusion】The BTN1A1-1 gene was more evolutionarily conservative than BTN1A1-2. The differential expressions of BTN1A1-1 and BTN1A1-2 in response to immune stimulation suggests that they may be functionally differentiated in the immune defence of S. aequifasciatus.

Background: Epidemiological research and systematic meta-analyses indicate a higher risk of B-cell lymphomas in patients with chronic hepatitis C virus (HCV) compared to non-infected individuals. However, the genetic links between HCV and these lymphomas remain under-researched. Methods: Mendelian randomization analysis was employed to explore the association between chronic hepatitis C (CHC) and B-cell lymphomas as well as chronic lymphocytic leukemia (CLL). Approximate Bayes Factor (ABF) localization analysis was conducted to find shared genetic variants that might connect CHC with B-cell lymphomas and chronic lymphocytic leukemia (CLL). Furthermore, The Variant Effect Predictor (VEP) was utilized to annotate the functional effects of the identified genetic variants. Results: Mendelian randomization revealed a significant association between CHC and increased diffuse large B cell lymphoma (DLBCL) risk (OR: 1.34; 95% CI: 1.01–1.78; P = 0.0397). Subsequent colocalization analysis pinpointed two noteworthy variants, rs17208853 (chr6:32408583) and rs482759 (chr6:32227240) between these two traits. The annotation of these variants through the VEP revealed their respective associations with the butyrophilin-like protein 2 (BTNL2) and notch receptor 4 (NOTCH4) genes, along with the long non-coding RNA (lncRNA) TSBP1-AS1. Conclusion: This research provides a refined genetic understanding of the CHC-DLBCL connection, opening avenues for targeted therapeutic research and intervention. [ABSTRACT FROM AUTHOR]

【Objective】Butyrophilin 1A1 (BTN1A1) gene from Symphysodon aequifasciatus was cloned and its express pattern under pathological infection was analyzed, to provide basis for better understanding of the function of BTN1A1 gene in S. aequifasciatu.【Method】The structure and evolutionary characteristics of two BTN1A1 genes (BTN1A1-1 and BTN1A1-2) were analyzed by bioinformatics analysis. Based on the transcriptome data of the skin of the S. aequifasciatu obtained at early stage, the CDS regions of BTN1A1-1 and BTN1A1-2 genes were used to design the primers for gene cloning. The expressions of BTN1A1-1 gene in various tissues and its expression pattern under the stimulus of Aeromonas hydrophila were analyzed by qRT-PCR.【Result】The ORF regions of BTN1A1-1 and BTN1A1-2 were 894 and 1 275 bp, encoding 298 and 424 amino acids, respectively. Both BTN1A1-1 and BTN1A1-2 had a classical structure of BTN, which contained a signal peptide, an Ig domain, an lg_like domain and a transmembrane domain. BTN1A1-2 also had a cytoplasmic domain. BTN1A1-1 showed a closer relationship with the genes found in cichlid fish. It shared the highest homology of 94.14% with the corresponding amino acid sequences of Archocentrus centrarchus; while BTN1A1-2 showed lower similarity with other types of fish, forming a special branch. The expressions of BTN1A1-1 and BTN1A1-2 were highly in gill, intestine and skin of S. aequifasciatu. The expression of BTN1A1-1 decreased significantly and then increased after the infection of A. hydrophila, while the expression of BTN1A1-2 increased significantly and then decreased.【Conclusion】The BTN1A1-1 gene was more evolutionarily conservative than BTN1A1-2. The differential expressions of BTN1A1-1 and BTN1A1-2 in response to immune stimulation suggests that they may be functionally differentiated in the immune defence of S. aequifasciatus. [ABSTRACT FROM AUTHOR]

Immuno-oncology has traditionally focused on conventional MHC-restricted αβ T cells. Yet, unconventional γδ T cells, which kill tumor cells in an MHC-unrestricted manner, display characteristics of effector activity and stemness without exhaustion and are nearly universally observed in human gynecologic malignancies, correlating with improved outcomes. These cells do not have a clear counterpart in mice but are also found in the healthy female reproductive tract. Interventions that modulate their in vivo activity, or cellular therapies utilizing γδ T cells as an allogeneic, "off-the-shelf" platform (e.g., for chimeric antigen receptor expression) hold significant potential against challenging tumors like ovarian cancer, which has been stubbornly resistant to the immune checkpoint inhibitors that change the landscape of other human tumors. Here, we discuss recent discoveries on the specific populations of γδ T cells that infiltrate human gynecologic cancers, their anti-tumor activity, and the prospect of redirecting their effector function against tumor cells to develop a new generation of immunotherapies that extends beyond the traditional αβ T cell-centric view of the field. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) has gained considerable scientific attention by playing a role in immunosuppression and tumorigenesis. Besides tumor cells, TME is composed of various other cell types, including cancer-associated fibroblasts (CAFs or MAFs when referring to melanoma-derived CAFs) and tumor-infiltrating lymphocytes (TILs), a subpopulation of which is labeled as γδ T cells. Since the current anti-cancer therapies using γδ T cells in various cancers have exhibited mixed treatment responses, to better understand the γδ T cell biology in melanoma, our research group aimed to investigate whether activated γδ T cells are capable of killing MAFs. To answer this question, we set up an in vitro platform using freshly isolated Vδ2-type γδ T cells and cultured MAFs that were biobanked from our melanoma patients. This study proved that the addition of zoledronic acid (1–2.5 µM) to the γδ T cells was necessary to drive MAFs into apoptosis. The MAF cytotoxicity of γδ T cells was further enhanced by using the stimulatory clone 20.1 of anti-BTN3A1 antibody but was reduced when anti-TCR γδ or anti-BTN2A1 antibodies were used. Since the administration of zoledronic acid is safe and tolerable in humans, our results provide further data for future clinical studies on the treatment of melanoma. [ABSTRACT FROM AUTHOR]

Butyrophilin (BTN1A1) gene is located in the neighborhood of a quantitative trait loci for milk production in bovine autosome 23. We verified the genetic variability of exon-3 in BTN1A1 and its association with milk production traits in Holstein Friesian crossbreds of Kerala. Genomic DNA was isolated and 94 bp fragment enclosing exon-3 was amplified by primers designed using PRIMER 3 based on reference sequence (GenBank NC_037350). Pooled amplicons were sequenced by Sanger's method and a novel single nucleotide polymorphism due to a transversion of guanine to adenine at position 21 of amplicon (G21A) leading to amino acid change arginine to glutamine was detected. The study population was genotyped by high-resolution melt curve analysis and revealed two genotypes with frequencies GG/0.84 and GA/0.14. The allele G was found to be the major one (G/0.93 and A/0.07). Moreover, association analysis of G21A with milk production traits was done using the General linear model-Analysis of Variance considering herd, season, and parity as non-genetic factors and milk production trait as a dependent variable. In analysis, animals with GA genotype were found to be having significantly higher (p ≤ 0.01) 305 day milk (GG:2720.74 ± 122.92 kg; GA:3250.20 ± 183.24 kg), fat (GG:106.55 ± 4.32 kg; GA:126.30 ± 13.35 kg), and SNF yield (GG: 211.52 ± 9.20 kg; GA: 246.90 ± 13.70 kg). However, GG (7.80 ± 0.04) genotype has significantly higher (p ≤ 0.05) SNF percent than GA (7.65 ± 0.07). Butyrophilin gene polymorphism G21A can be suggested as a molecular marker for future breeding programmes of cattle. [ABSTRACT FROM AUTHOR]

Immuno-oncology has traditionally focused on conventional MHC-restricted αβ T cells. Yet, unconventional γδ T cells, which kill tumor cells in an MHC-unrestricted manner, display characteristics of effector activity and stemness without exhaustion and are nearly universally observed in human gynecologic malignancies, correlating with improved outcomes. These cells do not have a clear counterpart in mice but are also found in the healthy female reproductive tract. Interventions that modulate their in vivo activity, or cellular therapies utilizing γδ T cells as an allogeneic, “off-the-shelf” platform (e.g., for chimeric antigen receptor expression) hold significant potential against challenging tumors like ovarian cancer, which has been stubbornly resistant to the immune checkpoint inhibitors that change the landscape of other human tumors. Here, we discuss recent discoveries on the specific populations of γδ T cells that infiltrate human gynecologic cancers, their anti-tumor activity, and the prospect of redirecting their effector function against tumor cells to develop a new generation of immunotherapies that extends beyond the traditional αβ T cell-centric view of the field.

Conventional immunohistochemistry methods though once fundamental for the individual staining of cell markers, have now been superseded by multispectral immunohistochemistry (mIHC). mIHC enables simultaneous detection of multiple cell markers in situ using single formalin-fixed paraffin-embedded (FFPE) tissue sections. In addition to conserving patient tissue specimens, the ability to visualise more than one marker on individual cells allows for further refining of cell phenotypes, and provides insight into cell-to-cell interactions and spatial arrangements across single tissue sections. Here, a comprehensive protocol is described for the in situ interrogation of γδ T cells and phosphoantigen-presenting butyrophilin (BTN) molecules (BTN2A1 and BTN3A1) in human FFPE tissue using Opal™ tyramide signal amplification (TSA)-based mIHC. It is demonstrated that an effectively optimised Opal™-TSA 7-marker [CD3, Pan-γδ T cell receptor (TCR), granzyme B, BTN2A1, BTN3A1, tumour marker, 4’,6-diamidino-2-phenylindole (DAPI)] mIHC panel can be used to define the presence, localisation, and activation status of γδ T cells and the BTN2A1 and BTN3A1 ligands.

The butyrophilin (BTN1A1) gene is found at a quantitative trait locus (QTL) in cattle for milk production traits. The effect of a single nucleotide polymorphism (SNP) A465G in exon 8, which causes a lysine to arginine transition, on milk production attributes in Holstein Friesian crossbred cattle from Kerala was investigated in this study (151 numbers). Using custom synthesised primers, a 90-bp fragment encompassing the polymorphic region was amplified from genomic DNA isolated.Genotyping was carried out by high resolution melt curve analysis (HRM) and two genotypes KK (0.25) and KL (0.75) were detected based on melting temperature and melt curve patterns.Sanger’s sequencing and sequence analysis of representative samples confirmed the genotypes.Chi-square test showed that the population was not distributed as per Hardy-Weinberg equilibrium(p≤0.05). The relationship between the A465G transition and milk production traits like 305 daymilk, fat, SNF yields, fat and SNF per cent was determined by general linear model-analysis of variance (GLM-ANOVA). In the model herd, season of calving, parity of animal (non-geneticfactors), and genotype were considered fixed variables and milk production traits as dependent variable. The study revealed significantly higher (p≤0.01) milk fat and SNF per cent for KK genotype(4.14±0.08 %; 7.86±0.06 %) than KL genotype (3.91±0.07 %; 7.73±0.05 %). The butyrophilin genepolymorphism (A465G) can be recommended as a marker for higher milk fat and SNF per cent infuture breeding programmes in crossbred cattle of Kerala.

Simple Summary: Different cells present in the tumor microenvironment can deeply influence both cancer spreading and the success of therapy in solid tumors, including colorectal carcinoma (CRC). In particular, tumor-associated fibroblasts (TAF) exert potent immunosuppressive effects leading to the impairment of anti-tumor surveillance and interfering with the function of therapeutic antibodies. Herein, we show that CRC-derived TAF can be turned by zoledronic acid (ZA), in soluble form or as antibody-drug conjugate (ADC), into efficient stimulators of anti-tumor lymphocytes. The ADC, made of the anti-EGFR cetuximab (Cet), used in CRC therapy, and ZA (Cet-ZA) can induce the proliferation of lymphocytes that become able to kill both tumor cells and TAF. The double result is a direct anti-cancer effect and the neutralization of the inhibitory activity exerted by its stroma. The major advantage of the Cet-ZA ADC formulation is the precise delivery of ZA to EGFR+ cells, targeting TAF (potentially immunosuppressive), besides CRC cells. Tumor-associated fibroblasts (TAF) exert immunosuppressive effects in colorectal carcinoma (CRC), impairing the recognition of tumor cells by effector lymphocytes, including Vδ2 T cells. Herein, we show that CRC-derived TAF can be turned by zoledronic acid (ZA), in soluble form or as antibody-drug conjugate (ADC), into efficient stimulators of Vδ2 T cells. CRC-TAF, obtained from patients, express the epidermal growth factor receptor (EGFR) and the butyrophilin family members BTN3A1/BTN2A1. These butyrophilins mediate the presentation of the phosphoantigens, accumulated in the cells due to ZA effect, to Vδ2 T cells. CRC-TAF exposed to soluble ZA acquired the ability to trigger the proliferation of Vδ2 T cells, in part represented by effector memory cells lacking CD45RA and CD27. In turn, expanded Vδ2 T cells exerted relevant cytotoxic activity towards CRC cells and CRC-TAF when primed with soluble ZA. Of note, also the ADC made of the anti-EGFR cetuximab (Cet) and ZA (Cet-ZA), that we recently described, induced the proliferation of anti-tumor Vδ2 T lymphocytes and their activation against CRC-TAF. These findings indicate that ZA can educate TAF to stimulate effector memory Vδ2 T cells; the Cet-ZA ADC formulation can lead to the precise delivery of ZA to EGFR+ cells, with a double targeting of TAF and tumor cells. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs), often adopting an immunosuppressive M2-like phenotype, correlate with unfavorable cancer outcomes. Our investigation unveiled elevated expression of the butyrophilin (BTN)2A1 in M2-like TAMs across diverse cancer types. We developed anti-BTN2A1 monoclonal antibodies (mAbs), and notably, one clone demonstrated a robust inhibitory effect on M2-like macrophage differentiation, inducing a shift toward an M1-like phenotype both in vitro and ex vivo in TAMs from patients with cancer. Macrophages treated with this anti-BTN2A1 mAb exhibited enhanced support for T cell proliferation and interferon-gamma (IFNγ) secretion. Mechanistically, BTN2A1 engagement induced spleen tyrosine kinase (SYK) recruitment, leading to sequential SYK and extracellular signal-regulated kinase (ERK) phosphorylation. Inhibition of SYK or ERK phosphorylation abolished M2 reprogramming upon BTN2A1 engagement. Our findings, derived from an analysis of macrophages from healthy donors and human tumors, underscore the pivotal role of BTN2A1 in immunosuppressive macrophage differentiation and function, offering potential applications in cancer immunotherapy. [Display omitted] • BTN2A1 highly expressed in TAMs of solid tumors • Anti-BTN2A1 mAb hinders in vitro M2-like macrophage differentiation • BTN2A1 interacts with SYK, inducing SYK and MAPK phosphorylation • SYK and ERK phosphorylation inhibition halts M2 reprogramming by BTN2A1 engagement Kerneur et al. pinpoint BTN2A1 as pivotal for normal and tumor-associated macrophage (TAM) plasticity, highly expressed by TAMs in solid tumors. They develop an anti-BTN2A1 antibody capable of shifting immunosuppressive M2-like macrophages to a pro-inflammatory M1-like state, unveiling essential downstream pathways crucial for such reprogramming. [ABSTRACT FROM AUTHOR]

Phosphoantigens (pAgs) induce conformational changes after binding to the intracellular region of BTN3A1 which result in its clustering with BTN2A1, forming an activating ligand for the Vγ9Vδ2 T cell receptor. Here, we designed a small panel of bulky analogs of the prototypical pAg (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) that contain an aromatic ring attached to the C-3 position in place of methyl group. These compounds bind with high affinity to BTN3A1 but fail to fully support its interaction with BTN2A1 and only partially trigger T cell activation relative to HMBPP. Furthermore, they can compete with HMBPP for cellular binding to BTN3A1 and reduce the cellular response to HMBPP, a classic partial agonist phenotype. Trifluoromethyl analog 6e was the weakest agonist but the strongest inhibitor of HMBPP ELISA response. Our study provides a rationale for the mode of action of pAg-induced γδ T cell activation and provides insights into other naturally occurring BTN proteins and their respective ligands. [Display omitted] • Bulky HMBPP analogs have lower maximal Vd2 T cell stimulation than HMBPP. • These partial agonists compete with HMBPP and reduce the cellular response to HMBPP. • 4-(trifluoromethyl)phenyl analog was the weakest agonist and strongest inhibitor. [ABSTRACT FROM AUTHOR]

The T cell receptor Vg9Vd2 T cells bridge innate and adaptive antimicrobial immunity in primates. These Vg9Vd2 T cells respond to phosphoantigens (pAgs) present in microbial or eukaryotic cells in a butyrophilin 3A1 (BTN3) and butyrophilin 2A1 (BTN2A1) dependent manner. In humans, the rapid expansion of circulating Vg9Vd2 T lymphocytes during several infections as well as their localization at the site of active disease demonstrates their important role in the immune response to infection. However, Vg9Vd2 T cell deficiencies have been observed in some infectious diseases such as active tuberculosis and chronic viral infections. In this review, we are providing an overview of the mechanisms of Vg9Vd2 T cell-mediated antimicrobial immunity. These cells kill infected cells mainly by releasing lytic mediators and pro-inflammatory cytokines and inducing target cell apoptosis. In addition, the release of chemokines and cytokines allows the recruitment and activation of immune cells, promoting the initiation of the adaptive immune response. Finaly, we also describe potential new therapeutic tools of Vg9Vd2 T cell-based immunotherapy that could be applied to emerging infections. [ABSTRACT FROM AUTHOR]

Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing inflammatory central nervous system disorder. Patients either have antibodies to aquaporin 4 (AQ4)/myelin oligodendrocyte glycoprotein (MOG) or are double seronegatives (DSN). Aim: We aimed at comparing the clinico-epidemiological features and outcome of the subgroups of NMOSD. Design: Prospective longitudinal observational study. Materials and Methods: NMOSD was diagnosed by using the 2006 Wingerchuk criteria. Patients diagnosed between September 2016 and August 2018 were prospectively followed up to July 2020. Acute episodes were treated with steroids, and immunomodulators were started in patients with aquaporin 4 IgG (anti-AQ4+) and in relapsing cases of anti- MOG+ and DSN groups. Disability was assessed by using the Expanded Disability Status Scale (EDSS). Comparisons were made between patients who were anti-AQ4 and anti-MOG positive and those with DSN. Statistical analysis was done by SPSS 20.0 software. Results: Among 13 patients, the female: male ratio was 1.16:1, and the mean age of disease onset was 9.65 ± 3.25 years. Overall, 15.38% patients were anti-AQ4+, 30.67% were anti-MOG+, 53.86% were DSN, 69.2% had relapsing disease, and 30.8% had monophasic disease (P = 0.11). The mean to relapse was 13.16±3.5 months; 61.5% patients had long segment myelitis and 53.86% had optic neuritis on their first presentation (P = 0.99). Cerebral syndrome occurred among one patient with anti-MOG+ and in three patients with DSN. The EDSS scores were significantly lower among patients who were anti-MOG+. Conclusion: The female: male ratio was more equitable and the age of disease onset was lower in our cohort compared with western data. There was no significant difference in the clinico-demographic characteristics among the three groups; however, outcome was better in the anti-MOG+ group. Rituximab was effective for recurrent relapses. [ABSTRACT FROM AUTHOR]

Vγ9Vδ2 T cells have been reported to participate to the immune response against infectious diseases such as the Q fever caused by Coxiella burnetii infection. Indeed, the number and proportion of Vγ9Vδ2 T cells are increased during the acute phase of Q fever. Human Vγ9Vδ2 T cell responses are triggered by phosphoantigens (pAgs) produced by pathogens and malignant cells, that are sensed via the membrane receptors butyrophilin-3A1 (BTN3A1) and -2A1 (BTN2A1). Here, by using CRISPR-Cas9 inactivation in THP-1 cells, we show that BTN3A and BTN2A are required to Vγ9Vδ2 T cell response to C. burnetii infection, though not directly involved in the infection process. Furthermore, C. burnetii -infected monocytes display increased BTN3A and BTN2A expression and induce Vγ9Vδ2 T cell activation that can be inhibited by specific antagonist mAb. More importantly, we show that the antimicrobial functions of Vγ9Vδ2 T cells towards C. burnetii are enhanced in the presence of an BTN3A activating antibody. This supports the role of Vγ9Vδ2 T cells in the control of C. burnetii infection and argues in favor of targeting these cells as an alternative treatment strategy for infectious diseases caused by intracellular bacteria. [ABSTRACT FROM AUTHOR]

Simple Summary: Research into the immunotherapeutic potential of T cells has predominantly focused on conventional alpha beta (αβ) T cells, which recognize peptide antigens presented by polymorphic major histocompatibility complex (MHC) class I and class II molecules. However, innate-like T cells, such as gamma delta (γδ) T cells, also play important roles in antitumor immunity. Here, we review the current understanding of γδ T cells in antitumor immunity and discuss strategies that could potentially maximize their potential in cancer immunotherapy. Gamma delta (γδ) T cells are a minor population of T cells that share adaptive and innate immune properties. In contrast to MHC-restricted alpha beta (αβ) T cells, γδ T cells are activated in an MHC-independent manner, making them ideal candidates for developing allogeneic, off-the-shelf cell-based immunotherapies. As the field of cancer immunotherapy progresses rapidly, different subsets of γδ T cells have been explored. In addition, γδ T cells can be engineered using different gene editing technologies that augment their tumor recognition abilities and antitumor functions. In this review, we outline the unique features of different subsets of human γδ T cells and their antitumor properties. We also summarize the past and the ongoing pre-clinical studies and clinical trials utilizing γδ T cell-based cancer immunotherapy. [ABSTRACT FROM AUTHOR]

The T cell receptor Vγ9Vδ2 T cells bridge innate and adaptive antimicrobial immunity in primates. These Vγ9Vδ2 T cells respond to phosphoantigens (pAgs) present in microbial or eukaryotic cells in a butyrophilin 3A1 (BTN3) and butyrophilin 2A1 (BTN2A1) dependent manner. In humans, the rapid expansion of circulating Vγ9Vδ2 T lymphocytes during several infections as well as their localization at the site of active disease demonstrates their important role in the immune response to infection. However, Vγ9Vδ2 T cell deficiencies have been observed in some infectious diseases such as active tuberculosis and chronic viral infections. In this review, we are providing an overview of the mechanisms of Vγ9Vδ2 T cell-mediated antimicrobial immunity. These cells kill infected cells mainly by releasing lytic mediators and pro-inflammatory cytokines and inducing target cell apoptosis. In addition, the release of chemokines and cytokines allows the recruitment and activation of immune cells, promoting the initiation of the adaptive immune response. Finaly, we also describe potential new therapeutic tools of Vγ9Vδ2 T cell-based immunotherapy that could be applied to emerging infections.

Vγ9Vδ2 T cells have been reported to participate to the immune response against infectious diseases such as the Q fever caused by Coxiella burnetii infection. Indeed, the number and proportion of Vγ9Vδ2 T cells are increased during the acute phase of Q fever. Human Vγ9Vδ2 T cell responses are triggered by phosphoantigens (pAgs) produced by pathogens and malignant cells, that are sensed via the membrane receptors butyrophilin-3A1 (BTN3A1) and -2A1 (BTN2A1). Here, by using CRISPR-Cas9 inactivation in THP-1 cells, we show that BTN3A and BTN2A are required to Vγ9Vδ2 T cell response to C. burnetii infection, though not directly involved in the infection process. Furthermore, C. burnetii-infected monocytes display increased BTN3A and BTN2A expression and induce Vγ9Vδ2 T cell activation that can be inhibited by specific antagonist mAb. More importantly, we show that the antimicrobial functions of Vγ9Vδ2 T cells towards C. burnetii are enhanced in the presence of an BTN3A activating antibody. This supports the role of Vγ9Vδ2 T cells in the control of C. burnetii infection and argues in favor of targeting these cells as an alternative treatment strategy for infectious diseases caused by intracellular bacteria.

Butyrophilins (BTN) are relatives of the B7 family (e.g., CD80, PD-L1). They fulfill a wide range of functions including immunomodulation and bind to various receptors such as the γδ T cell receptor (γδTCR) and small molecules. One intensively studied molecule is BTN3A1, which binds via its cytoplasmic B30.2 domain, metabolites of isoprenoid synthesis, designated as phosphoantigen (PAg), The enrichment of PAgs in tumors or infected cells is sensed by Vγ9Vδ2 T cells, leading to the proliferation and execution of effector functions to remove these cells. This article discusses the contribution of BTNs, the related BTNL molecules and SKINT1 to the development, activation, and homeostasis of γδ T cells and their immunomodulatory potential, which makes them interesting targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Butyrophilins (BTN) are relatives of the B7 family (e.g., CD80, PD-L1). They fulfill a wide range of functions including immunomodulation and bind to various receptors such as the γδ T cell receptor (γδTCR) and small molecules. One intensively studied molecule is BTN3A1, which binds via its cytoplasmic B30.2 domain, metabolites of isoprenoid synthesis, designated as phosphoantigen (PAg), The enrichment of PAgs in tumors or infected cells is sensed by Vγ9Vδ2 T cells, leading to the proliferation and execution of effector functions to remove these cells. This article discusses the contribution of BTNs, the related BTNL molecules and SKINT1 to the development, activation, and homeostasis of γδ T cells and their immunomodulatory potential, which makes them interesting targets for therapeutic intervention.

The article focuses on a clinical note describing a case of anti-MOG antibody-positive meningoencephalitis in a four-year-old child, challenging the conventional association of MOGAD with demyelinating lesions. Topics discussed include the rarity of MOGAD in preschool children with aseptic meningitis and the potential effectiveness of steroid therapy in such cases, emphasizing the importance of anti-MOG antibody measurement for diagnosis and treatment decisions.

Innate lymphoid cells (ILC) not only are responsible for shaping the innate immune response but also actively modulate T cell responses. However, the molecular processes regulating ILC-T cell interaction are not yet completely understood. The protein butyrophilin 2a2 (Btn2a2), a co-stimulatory molecule first identified on antigen-presenting cells, has a pivotal role in the maintenance of T cell homeostasis, but the main effector cell and the respective ligands remain elusive. We analyzed the role of Btn2a2 in the ILC-T cell cross talk. We found that the expression of Btn2a2 is upregulated in ILC2 following stimulation with IL-33/IL-25/TSLP. In vitro and in vivo experiments indicated that lack of Btn2a2 expression on ILC2 resulted in elevated T cell responses. We observed an enhanced proliferation of T cells as well as increased secretion of the type 2 cytokines IL-4/IL-5/IL-13 following cocultures with Btn2a2-deficient ILC2. In vivo transfer experiments confirmed the regulatory role of Btn2a2 on ILC2 as Btn2a2-deficient ILC2 induced stronger T cell responses and prevented chronic helminth infections. Taken together, we identified Btn2a2 as a significant player in the regulation of ILC2–T cell interactions. [ABSTRACT FROM AUTHOR]

Butyrophilin 1A1 (BTN1A1) is implicated in the secretion of lipid droplets from mammary epithelial cells as a membrane receptor, which forms a secretion complex with the redox enzyme, xanthine oxidoreductase (XDH). The first evidence that BTN1A1 functions in this process was the generation of Btn1a1−/− mouse lines, in which lipid secretion was disrupted and large unstable droplets were released into alveolar spaces with fragmented surface membranes. We have revisited one of these mutant mouse lines using RNAseq and proteomic analysis to assess the consequences of ablating the Btn1a1 gene on the expression of other genes and proteins. Disruption of intact Btn1a1 protein expression led to a large build‐up of Xdh in the cytoplasm, induction of acute phase response genes and Lif‐activation of Stat3 phosphorylation. At peak lactation, approx. 10% of the cells were dying, as assessed by TUNEL‐analysis of nuclear DNA. Possible cell death pathways included expression of caspase 8 and activated caspase 3, autophagy, Slc5a8‐mediated inactivation of survivin (Birc5), and pStat3‐mediated lysosomal lysis, the latter of which is the principal death route in involuting wild type cells. Milk secretion was prolonged by renewal of the secretory epithelium, as evidenced by the upregulation of Ki67 in approx. 10% of cell nuclei and expression of cyclins and Fos/Jun. These data highlight the plasticity of the mammary epithelium and the importance of functional BTN1A1 expression for maintenance of terminally differentiated secretory cells and optimal milk production throughout lactation. [ABSTRACT FROM AUTHOR]

Innate lymphoid cells (ILC) not only are responsible for shaping the innate immune response but also actively modulate T cell responses. However, the molecular processes regulating ILC-T cell interaction are not yet completely understood. The protein butyrophilin 2a2 (Btn2a2), a co-stimulatory molecule first identified on antigen-presenting cells, has a pivotal role in the maintenance of T cell homeostasis, but the main effector cell and the respective ligands remain elusive. We analyzed the role of Btn2a2 in the ILC-T cell cross talk. We found that the expression of Btn2a2 is upregulated in ILC2 following stimulation with IL-33/IL-25/TSLP. In vitro and in vivo experiments indicated that lack of Btn2a2 expression on ILC2 resulted in elevated T cell responses. We observed an enhanced proliferation of T cells as well as increased secretion of the type 2 cytokines IL-4/IL-5/IL-13 following cocultures with Btn2a2-deficient ILC2. In vivo transfer experiments confirmed the regulatory role of Btn2a2 on ILC2 as Btn2a2-deficient ILC2 induced stronger T cell responses and prevented chronic helminth infections. Taken together, we identified Btn2a2 as a significant player in the regulation of ILC2–T cell interactions.

The article presents a case study of a nine-year-old boy with symptoms resembling Adrenoleukodystrophy (ALD) but later diagnosed with Myelin Oligodendrocyte Glycoprotein (MOG)-antibody-associated demyelination. It emphasizes the importance of considering MOGAD in atypical neurological presentations for accurate diagnosis and timely treatment to improve clinical outcomes.

Gamma-delta (γδ) T cells express T cell receptors (TCR) that are preconfigured to recognize signs of pathogen infection. In primates, γδ T cells expressing the Vγ9Vδ2 TCR innately recognize (E)-4-hydroxy-3-methyl-but- 2-enyl pyrophosphate (HMBPP), a product of the 2-C-methyl-D-erythritol 4- phosphate (MEP) pathway in bacteria that is presented in infected cells via interaction with members of the B7 family of costimulatory molecules butyrophilin (BTN) 3A1 and BTN2A1. In humans, Listeria monocytogenes (Lm) vaccine platforms have the potential to generate potent Vγ9Vδ2 T cell recognition. To evaluate the activation of Vγ9Vδ2 T cells by Lm-infected human monocyte-derived dendritic cells (Mo-DC) we engineered Lm strains that lack components of the MEP pathway. Direct infection of Mo-DC with these bacteria were unchanged in their ability to activate CD107a expression in Vγ9Vδ2 T cells despite an inability to synthesize HMBPP. Importantly, functional BTN3A1 was essential for this activation. Unexpectedly, we found that cytoplasmic entry of Lm into human dendritic cells resulted in upregulation of cholesterol metabolism in these cells, and the effect of pathway regulatory drugs suggest this occurs via increased synthesis of the alternative endogenous Vγ9Vδ2 ligand isoprenyl pyrophosphate (IPP) and/or its isomer dimethylallyl pyrophosphate (DMAPP). Thus, following direct infection, host pathways regulated by cytoplasmic entry of Lm can trigger Vγ9Vδ2 T cell recognition of infected cells without production of the unique bacterial ligand HMBPP. [ABSTRACT FROM AUTHOR]

Tissue-resident γδ intraepithelial lymphocytes (IELs) orchestrate innate and adaptive immune responses to maintain intestinal epithelial barrier integrity. Epithelia-specific butyrophilin-like (Btnl) molecules induce perinatal development of distinct Vγ TCR+ IELs, however, the mechanisms that control γδ IEL maintenance within discrete intestinal segments are unclear. Here, we show that Btnl2 suppressed homeostatic proliferation of γδ IELs preferentially in the ileum. High throughput transcriptomic characterization of site-specific Btnl2-KO γδ IELs reveals that Btnl2 regulated the antimicrobial response module of ileal γδ IELs. Btnl2 deficiency shapes the TCR specificities and TCRγ/δ repertoire diversity of ileal γδ IELs. During DSS-induced colitis, Btnl2-KO mice exhibit increased inflammation and delayed mucosal repair in the colon. Collectively, these data suggest that Btnl2 fine-tunes γδ IEL frequencies and TCR specificities in response to site-specific homeostatic and inflammatory cues. Hence, Btnl-mediated targeting of γδ IEL development and maintenance may help dissect their immunological functions in intestinal diseases with segment-specific manifestations. Panea et al showed that epithelia-specific butyrophilinlike 2 (Btnl2) suppressed homeostatic proliferation of γδ intraepithelial lymphocytes (IELs) preferentially in the ileum and used high throughput transcriptomic characterization of Btnl2-deficient γδ IELs to demonstrate that Btnl2 impacts γδ TCR specificities and repertoire diversity of ileal γδ IELs. In addition, they showed that Btnl2-deficient mice exhibited increased inflammation and delayed mucosal repair in the colon, suggesting that it plays a key immunological function in intestinal diseases. [ABSTRACT FROM AUTHOR]

The development of immune checkpoint inhibitors (ICI) has dramatically changed the landscape of therapies for metastatic renal cell carcinoma. However, many patients do not benefit from such therapy and prognostic or predictive validated biomarker validated for ICI are still needed to better select and treat patient. Plasmatic soluble immune checkpoints have been described as potential immune biomarkers in hematological malignancies and solids tumors, then, we would like to explore the prognostic value of different soluble immune checkpoints in patients with mRCC treated with nivolumab after TKI. We prospectively collected plasma samples before nivolumab infusion from 38 patients previously treated for mRCC with TKI at Paoli-Calmettes Institute, from the NIVOREN GETUG-AFU 26 study (NCT03013335). Enzyme-linked immunosorbent assays (ELISA) were performed for soluble forms of PD-1, PD-L1, global BTN3, BTLA, BTN3A1 and BTN2A1. Among the different soluble checkpoints analyzed, only high baseline plasmatic level of BTN2A1 was significantly associated with shorter PFS: median PFS was 3.95 months for sBTN2A1high vs 14.30 months for sBTN2A1low (sBTN2A1 cut-off: 6.7ng/mL; HR = 2.26, 95%CI [0.68 – 4.60], p = 0.0307). There was no statistical difference in OS between sBTN2A1high and sBTN2A1low. Our results suggest that the baseline level of plasmatic BTN2A1 could be an independent prognosis factor of PFS after nivolumab for pre-treated patient with mRCC. However, these results need to be validated in a larger prospective cohort and the biological role of BTN subfamily and γδ T cell immunity in mRCC must be elucidated.

The development of immune checkpoint inhibitors (ICI) has dramatically changed the landscape of therapies for metastatic renal cell carcinoma. However, many patients do not benefit from such therapy and prognostic or predictive validated biomarker validated for ICI are still needed to better select and treat patient. Plasmatic soluble immune checkpoints have been described as potential immune biomarkers in hematological malignancies and solids tumors, then, we would like to explore the prognostic value of different soluble immune checkpoints in patients with mRCC treated with nivolumab after TKI. We prospectively collected plasma samples before nivolumab infusion from 38 patients previously treated for mRCC with TKI at Paoli-Calmettes Institute, from the NIVOREN GETUG-AFU 26 study (NCT03013335). Enzyme-linked immunosorbent assays (ELISA) were performed for soluble forms of PD-1, PD-L1, global BTN3, BTLA, BTN3A1 and BTN2A1. Among the different soluble checkpoints analyzed, only high baseline plasmatic level of BTN2A1 was significantly associated with shorter PFS: median PFS was 3.95 months for sBTN2A1high vs 14.30 months for sBTN2A1low (sBTN2A1 cut-off: 6.7ng/mL; HR = 2.26, 95%CI [0.68 – 4.60], p = 0.0307). There was no statistical difference in OS between sBTN2A1high and sBTN2A1low. Our results suggest that the baseline level of plasmatic BTN2A1 could be an independent prognosis factor of PFS after nivolumab for pre-treated patient with mRCC. However, these results need to be validated in a larger prospective cohort and the biological role of BTN subfamily and γδ T cell immunity in mRCC must be elucidated. [ABSTRACT FROM AUTHOR]

γδ T cells are a small subset of unconventional T cells that are enriched in the mucosal areas, and are responsible for pathogen clearance and maintaining integrity. However, the role of γδ T cells in head and neck squamous cell carcinoma (HNSCC) is largely unknown. Here, by using RNA-seq data from The Cancer Genome Atlas (TCGA), we discovered that HNSCC patients with higher levels of γδ T cells were positively associated with lower clinical stages and better overall survival, and high abundance of γδ T cells was positively correlated with CD8+/CD4+ T cell infiltration. Gene ontology and pathway analyses showed that genes associated with T cell activation, proliferation, effector functions, cytotoxicity, and chemokine production were enriched in the group with a higher γδ T cell abundance. Furthermore, we found that the abundance of γδ T cells was positively associated with the expression of the butyrophilin (BTN) family proteins BTN3A1/BTN3A2/BTN3A3 and BTN2A1, but only MICB, one of the ligands of NKG2D, was involved in the activation of γδ T cells, indicating that the BTN family proteins might be involved in the activation and proliferation of γδ T cells in the tumor microenvironment of HNSCC. Our results indicated that γδ T cells, along with their ligands, are promising targets in HNSCC with great prognostic values and treatment potentials.

The butyrophilins (BTNs) represent a unique family of immunoglobulin. They were considered to be involved in milk lactation after their discovery in 1981. With the development of research, an increasing number of research revealed that BTNs play important roles in immune regulation [1992–2019]. Our research aimed to summarize the BTN research status and their relationship with lung cancers and breast cancers by bibliometrics and bioinformatics methods. Our results indicate that the researches on immune-regulatory functions of BTNs gradually developed from 1992 to 2006, whereas they increased quickly after 2007. There are international cooperations among 56 countries, of which the United States is the most active one with the highest number of studies as well as highest citations. By coauthorship and cocitation analysis, we showed that Adrian Hayday, who is active in γδ T-cell field, was an active author in BTN publications with average year of 2015 and led a subfield. By keywords co-occurrence analysis, we found that γδ T cell, which is an important cancer immune regulator, is one important hotspot. Finally, we found that several BTN members' expression levels were significantly correlated with prognosis of lung cancer and breast cancer patients. Thus, these BTNs might play immune regulatory effects and could serve as potential biomarkers for cancer.

Indian milch bovines comprises of 58.56% of total livestock population (512.05 million) in the country and primarily includes native and crossbred cattle (37.28%) and water buffaloes (21.28%). Milk and milk products are essential food items of Indian diet especially in children, old and senile. Milk fat is an important constituent of milk and has an economic value and its percentage in milk varies betweem species and breeds within species. Butyrophilin (BTN1A1) a membrane protein regulates secretion of lipids and size of a fat globule in milk. Present study was conducted in 538 bovines of 11 breeds/populations adapted to different parts of India, with an aim to screen and determine the major allele of BTN1A1 gene using PCR-RFLP based test. Results indicate that exon 8 of BTN1A1 gene is polymorphic in Tharparkar, Sahiwal, Jhari and Belahi populations of native cattle and Holstein Friesian and Jersey crossbreds where as the same exon was monomorphic in Murrah, Chilika, Gojri, Chhattisgarhi and Bargur populations of water buffalo. We conclude that variations in BTN1A1 gene can serve as an excellent genetic marker while selecting cows for higher milk fat and can be applied while formulating their breeding plans.

A case study of a 44‑year‑old lady presenting with 1‑week history of progressive left upper and lower limb weakness, without any craniobulbar symptoms or symptoms of raised intracranial pressure. Topics include treatment with pulsed intravenous methylprednisolone and maintenance oral steroids, she showed dramatic improvement in neurological status; and history of bilateral optic neuritis, there was a high suspicion of demyelinating disorder like neuromyelitis optica or anti‑MOG syndrome.

Distinct innate‐like and adaptive‐like immunobiological paradigms are emerging for human γδ T cells, supported by a combination of immunophenotypic, T cell receptor (TCR) repertoire, functional, and transcriptomic data. Evidence of the γδ TCR/ligand recognition modalities that respective human subsets utilize is accumulating. Although many questions remain unanswered, one superantigen‐like modality features interactions of germline‐encoded regions of particular TCR Vγ regions with specific BTN/BTNL family members and apparently aligns with an innate‐like biology, albeit with some scope for clonal amplification. A second involves CDR3‐mediated γδ TCR interaction with diverse ligands and aligns with an adaptive‐like biology. Importantly, these unconventional modalities provide γδ T cells with unique recognition capabilities relative to αβ T cells, B cells, and NK cells, allowing immunosurveillance for signatures of "altered self" on target cells, via a membrane‐linked γδ TCR recognizing intact non‐MHC proteins on the opposing cell surface. In doing so, they permit cellular responses in diverse situations including where MHC expression is compromised, or where conventional adaptive and/or NK cell‐mediated immunity is suppressed. γδ T cells may therefore utilize their TCR like a cell‐surface Fab repertoire, somewhat analogous to engineered chimeric antigen receptor T cells, but additionally integrating TCR signaling with parallel signals from other surface immunoreceptors, making them multimolecular sensors of cellular stress. [ABSTRACT FROM AUTHOR]

Both, jawless and jawed vertebrates possess three lymphocyte lineages defined by highly diverse antigen receptors: Two T‐cell‐ and one B‐cell‐like lineage. In both phylogenetic groups, the theoretically possible number of individual antigen receptor specificities can even outnumber that of lymphocytes of a whole organism. Despite fundamental differences in structure and genetics of these antigen receptors, convergent evolution led to functional similarities between the lineages. Jawed vertebrates possess αβ and γδ T‐cells defined by eponymous αβ and γδ T‐cell antigen receptors (TCRs). "Conventional" αβ T‐cells recognize complexes of Major Histocompatibility Complex (MHC) class I and II molecules and peptides. Non‐conventional T‐cells, which can be αβ or γδ T‐cells, recognize a large variety of ligands and differ strongly in phenotype and function between species and within an organism. This review describes similarities and differences of non‐conventional T‐cells of various species and discusses ligands and functions of their TCRs. A special focus is laid on Vγ9Vδ2 T‐cells whose TCRs act as sensors for phosphorylated isoprenoid metabolites, so‐called phosphoantigens (PAg), associated with microbial infections or altered host metabolism in cancer or after drug treatment. We discuss the role of butyrophilin (BTN)3A and BTN2A1 in PAg‐sensing and how species comparison can help in a better understanding of this human Vγ9Vδ2 T‐cell subset. [ABSTRACT FROM AUTHOR]

γδ T cells are a small subset of unconventional T cells that are enriched in the mucosal areas, and are responsible for pathogen clearance and maintaining integrity. However, the role of γδ T cells in head and neck squamous cell carcinoma (HNSCC) is largely unknown. Here, by using RNA-seq data from The Cancer Genome Atlas (TCGA), we discovered that HNSCC patients with higher levels of γδ T cells were positively associated with lower clinical stages and better overall survival, and high abundance of γδ T cells was positively correlated with CD8+/CD4+ T cell infiltration. Gene ontology and pathway analyses showed that genes associated with T cell activation, proliferation, effector functions, cytotoxicity, and chemokine production were enriched in the group with a higher γδ T cell abundance. Furthermore, we found that the abundance of γδ T cells was positively associated with the expression of the butyrophilin (BTN) family proteins BTN3A1/BTN3A2/BTN3A3 and BTN2A1, but only MICB, one of the ligands of NKG2D, was involved in the activation of γδ T cells, indicating that the BTN family proteins might be involved in the activation and proliferation of γδ T cells in the tumor microenvironment of HNSCC. Our results indicated that γδ T cells, along with their ligands, are promising targets in HNSCC with great prognostic values and treatment potentials. [ABSTRACT FROM AUTHOR]

Gamma delta (gd) T cells infiltrate most human tumors, but current immunotherapies fail to exploit their in situ major histocompatibility complex–independent tumoricidal potential. Activation of gd T cells can be elicited by butyrophilin and butyrophilin-like molecules that are structurally similar to the immunosuppressive B7 family members, yet how they regulate and coordinate ab and gd T cell responses remains unknown. Here, we report that the butyrophilin BTN3A1 inhibits tumor-reactive ab T cell receptor activation by preventing segregation of N-glycosylated CD45 from the immune synapse. Notably, CD277-specific antibodies elicit coordinated restoration of ab T cell effector activity and BTN2A1-dependent gd lymphocyte cytotoxicity against BTN3A1+ cancer cells, abrogating malignant progression. Targeting BTN3A1 therefore orchestrates cooperative killing of established tumors by ab and gd T cells and may present a treatment strategy for tumors resistant to existing immunotherapies. [ABSTRACT FROM AUTHOR]

The butyrophilins (BTNs) represent a unique family of immunoglobulin. They were considered to be involved in milk lactation after their discovery in 1981. With the development of research, an increasing number of research revealed that BTNs play important roles in immune regulation [1992–2019]. Our research aimed to summarize the BTN research status and their relationship with lung cancers and breast cancers by bibliometrics and bioinformatics methods. Our results indicate that the researches on immune-regulatory functions of BTNs gradually developed from 1992 to 2006, whereas they increased quickly after 2007. There are international cooperations among 56 countries, of which the United States is the most active one with the highest number of studies as well as highest citations. By coauthorship and cocitation analysis, we showed that Adrian Hayday, who is active in γδ T-cell field, was an active author in BTN publications with average year of 2015 and led a subfield. By keywords co-occurrence analysis, we found that γδ T cell, which is an important cancer immune regulator, is one important hotspot. Finally, we found that several BTN members' expression levels were significantly correlated with prognosis of lung cancer and breast cancer patients. Thus, these BTNs might play immune regulatory effects and could serve as potential biomarkers for cancer. [ABSTRACT FROM AUTHOR]

Vγ9VΣ2 T cells are a major γΣ T cell population in the human blood expressing a characteristic Vγ9JP rearrangement paired with VΣ2. This cell subset is activated in a TCR-dependent and MHCunrestricted fashion by so-called phosphoantigens (PAgs). PAgs can be microbial [(E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate, HMBPP] or endogenous (isopentenyl pyrophosphate, IPP) and PAg sensing depends on the expression of B7-like butyrophilin (BTN3A, CD277) molecules. IPP increases in some transformed or aminobisphosphonate-treated cells, rendering those cells a target for Vγ9VΣ2 T cells in immunotherapy. Yet, functional Vγ9VΣ2 T cells have only been described in humans and higher primates. Using a genome-based study, we showed in silico translatable genes encoding Vγ9, VΣ2, and BTN3 in a few nonprimate mammalian species. Here, with the help of new monoclonal antibodies, we directly identified a T cell population in the alpaca (Vicugna pacos), which responds to PAgs in a BTN3-dependent fashion and shows typical TRGV9- and TRDV2-like rearrangements. T cell receptor (TCR) transductants and BTN3-deficient human 293T cells reconstituted with alpaca or human BTN3 or alpaca/human BTN3 chimeras showed that alpaca Vγ9VΣ2 TCRs recognize PAg in the context of human and alpaca BTN3. Furthermore, alpaca BTN3 mediates PAg recognition much better than human BTN3A1 alone and this improved functionality mapped to the transmembrane/cytoplasmic part of alpaca BTN3. In summary, we found remarkable similarities but also instructive differences of PAg-recognition by human and alpaca, which help in better understanding the molecular mechanisms controlling the activation of this prominent population of γΣ T cells. [ABSTRACT FROM AUTHOR]

Abstract Despite playing critical roles in the immune response and having significant potential in immunotherapy, γδ T cells have garnered little of the limelight. One major reason for this paradox is that their antigen recognition mechanisms are largely unknown, limiting our understanding of their biology and our potential to modulate their activity. One of the best-studied γδ subsets is the human Vγ9Vδ2T cell population, which predominates in peripheral blood and can combat both microbial infections and cancers. Although it has been known for decades that Vγ9Vδ2T cells respond to the presence of small pyrophosphate-based metabolites, collectively named phosphoantigens (pAgs), derived from microbial sources or malignant cells, the molecular basis for this response has been unclear. A major breakthrough in this area came with the identification of the Butyrophilin 3A (BTN3A) proteins, members of the Butyrophilin/Butyrophilin-like protein family, as mediators between pAgs and Vγ9Vδ2T cells. In this article, we review the most recent studies regarding pAg activation of human Vγ9Vδ2T cells, mainly focusing on the role of BTN3A as the pAg sensing molecule, as well as its potential impact on downstream events of the activation process. [ABSTRACT FROM AUTHOR]

Butyrophilin and butyrophilin-like proteins select γδ T cells and direct the migration of γδ T cell subsets to distinct anatomical sites. γδ T cells expressing Vδ2 paired with Vγ9 (Vγ9Vδ2 T cells) are the predominant γδ T cell type in human peripheral blood. Vγ9Vδ2 T cells, which cannot be studied easily in vivo because they do not exist in rodents, are often referred to as innate-like T cells. The genetically recombined γδ T cell receptor (TCR) that responds to isoprenoid-derived pyrophosphates (phosphoantigens) produced by infected and malignant cells in a butyrophilin-dependent manner qualifies them as therapeutically relevant components of the adaptive immune system. On the other hand, cell-surface proteins such as the C-type lectin CD161 mark a functional phenotype of Vγ9Vδ2 T cells that mediates TCR-independent innate-like responses. Moreover, CD56 (neural cell adhesion molecule, NCAM) and the G protein-coupled receptor GPR56 define Vγ9Vδ2 T cells with increased cytolytic potential and, like CD161, may also be expressed by dendritic cells, principally facilitating the generation of an innate-like immunological synapse. In this review, we summarise current knowledge of Vγ9Vδ2 T cell functional phenotypes that are critical to lymphoid stress surveillance.

Vγ9Vδ2 T cells represent a major unconventional γδ T cell subset located in the peripheral blood of adults in humans and several non-human primates. Lymphocytes that constitute this transitional subset can sense subtle level changes of intracellular phosphorylated intermediates of the isoprenoid biosynthesis pathway (phosphoantigens, pAg), such as isopentenyl pyrophosphate, during cell stress events. This unique antigenic activation process operates in a rigorous framework that requires the expression of butyrophilin 3A1 (BTN3A1/CD277) molecules, which are type I glycoproteins that belong to the B7 family. Several studies have further shown that pAg specifically bind to the intracellular B30.2 domain of BTN3A1 linked to the antigenic activation of Vγ9Vδ2 T cells. Here, we highlight the recent advances in BTN3A1 dynamics induced upon the binding of pAg and the contribution of the different subunits to this activation process. Recent reports support that conformational modifications of BTN3A1 might represent a key step in the detection of infection or tumorigenesis by Vγ9Vδ2 T cells. A better understanding of this mechanism will help optimize novel immunotherapeutical approaches that target defined functions of this unique γδ T cell subset.

Keywords: T cells; cancer; butyrophilin; immunotherapy; bisphoshonates EN T cells cancer butyrophilin immunotherapy bisphoshonates N.PAG N.PAG 3 11/25/20 20201120 NES 201120 Since the discovery of T cells, this rare and unique component of the immune system has been recognized for its potential in cancer immunology and immunotherapy. The molecular targets of TCRs and functions of these cells have largely eluded researchers, partly because T cell recognition of cancer cells and their response kinetics are very different to T cells ([7], [8]). Whether CAR T cells will overcome the scarce infiltration of tumors by classical CAR T cells remains to tested and might depend on the type of T cells (i.e. V 1 cells versus V 2 cells), which have naturally different homing tissues. [Extracted from the article]

A strategy for the direct functionalization strategy of inertial dialkyl phosphonates with hydroxy compounds to afford diverse mixed phosphonates with good yields and functional‐group tolerance has been developed. Mechanistic investigations involving both NMR studies and DFT studies suggest that an unprecedented highly reactive PV species (phosphoryl pyridin‐1‐ium salt), a key intermediate for this new synthetic transformation, is generated in situ from dialkyl phosphonate in the presence of Tf2O/pyridine. Mild thing, you make my heart sing: The application of Tf2O to phosphorus chemistry was expanded to the generation of electrophilic P‐species. A metal‐free activation of stable dialkyl phosphonates was developed that enables the synthesis of diverse mixed phosphonates. The reaction proceeds under mild conditions and exhibits a broad substrate scope and excellent functional‐group tolerance. NMR studies and DFT calculations provide insight into the mechanism. [ABSTRACT FROM AUTHOR]