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1.
J Immunother Cancer ; 12(4)2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38621815

RESUMO

BACKGROUND: Cancer immunotherapy including immune checkpoint inhibitors is only effective for a limited population of patients with cancer. Therefore, the development of novel cancer immunotherapy is anticipated. In preliminary studies, we demonstrated that tetracyclines enhanced T-cell responses. Therefore, we herein investigated the efficacy of tetracyclines on antitumor T-cell responses by human peripheral T cells, murine models, and the lung tumor tissues of patients with non-small cell lung cancer (NSCLC), with a focus on signaling pathways in T cells. METHODS: The cytotoxicity of peripheral and lung tumor-infiltrated human T cells against tumor cells was assessed by using bispecific T-cell engager (BiTE) technology (BiTE-assay system). The effects of tetracyclines on T cells in the peripheral blood of healthy donors and the tumor tissues of patients with NSCLC were examined using the BiTE-assay system in comparison with anti-programmed cell death-1 (PD-1) antibody, nivolumab. T-cell signaling molecules were analyzed by flow cytometry, ELISA, and qRT-PCR. To investigate the in vivo antitumor effects of tetracyclines, tetracyclines were administered orally to BALB/c mice engrafted with murine tumor cell lines, either in the presence or absence of anti-mouse CD8 inhibitors. RESULTS: The results obtained revealed that tetracyclines enhanced antitumor T-cell cytotoxicity with the upregulation of granzyme B and increased secretion of interferon-γ in human peripheral T cells and the lung tumor tissues of patients with NSCLC. The analysis of T-cell signaling showed that CD69 in both CD4+ and CD8+ T cells was upregulated by minocycline. Downstream of T-cell receptor signaling, Zap70 phosphorylation and Nur77 were also upregulated by minocycline in the early phase after T-cell activation. These changes were not observed in T cells treated with anti-PD-1 antibodies under the same conditions. The administration of tetracyclines exhibited antitumor efficacy with the upregulation of CD69 and increases in tumor antigen-specific T cells in murine tumor models. These changes were canceled by the administration of anti-mouse CD8 inhibitors. CONCLUSIONS: In conclusion, tetracyclines enhanced antitumor T-cell immunity via Zap70 signaling. These results will contribute to the development of novel cancer immunotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Camundongos , Humanos , Linfócitos T CD8-Positivos , Minociclina/metabolismo , Minociclina/farmacologia , Transdução de Sinais , Ativação Linfocitária
2.
Immunohorizons ; 8(4): 326-338, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38625120

RESUMO

The BCR allows for Ag-driven B cell activation and subsequent Ag endocytosis, processing, and presentation to recruit T cell help. Core drivers of BCR signaling and endocytosis are motifs within the receptor's cytoplasmic tail (primarily CD79). However, BCR function can be tuned by other proximal cellular elements, such as CD20 and membrane lipid microdomains. To identify additional proteins that could modulate BCR function, we used a proximity-based biotinylation technique paired with mass spectrometry to identify molecular neighbors of the murine IgM BCR. Those neighbors include MHC class II molecules, integrins, various transporters, and membrane microdomain proteins. Class II molecules, some of which are invariant chain-associated nascent class II, are a readily detected BCR neighbor. This finding is consistent with reports of BCR-class II association within intracellular compartments. The BCR is also in close proximity to multiple proteins involved in the formation of membrane microdomains, including CD37, raftlin, and Ig superfamily member 8. Known defects in T cell-dependent humoral immunity in CD37 knockout mice suggest a role for CD37 in BCR function. In line with this notion, CRISPR-based knockout of CD37 expression in a B cell line heightens BCR signaling, slows BCR endocytosis, and tempers formation of peptide-class II complexes. These results indicate that BCR molecular neighbors can impact membrane-mediated BCR functions. Overall, a proximity-based labeling technique allowed for identification of multiple previously unknown BCR molecular neighbors, including the tetraspanin protein CD37, which can modulate BCR function.


Assuntos
Imunidade Humoral , Proteínas de Membrana , Animais , Camundongos , Linhagem Celular , Ativação Linfocitária , Camundongos Knockout , Receptores de Antígenos de Linfócitos B
3.
Crit Rev Immunol ; 44(5): 87-98, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38618731

RESUMO

Despite advancements in the field of cancer therapeutics, the five-year survival rate remains low in oral cancer patients. Therefore, the effective therapeutics are needed against oral cancer. Also, several studies including ours, have shown severely suppressed function and number of NK cells in oral cancer patients. In this review, we discuss the approach to inhibit the tumor growth and metastasis by direct killing or NK cell-mediated tumor differentiation. This review also provides an overview on supercharging NK cells using osteoclasts and probiotic bacteria, and their efficacy as cancer immunotherapeutic in humanized-BLT mice.


Assuntos
Neoplasias Bucais , Humanos , Animais , Camundongos , Neoplasias Bucais/terapia , Imunoterapia , Diferenciação Celular , Células Matadoras Naturais , Ativação Linfocitária
4.
Cell Mol Biol Lett ; 29(1): 52, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38609863

RESUMO

T cell immunity is central to contemporary cancer and autoimmune therapies, encompassing immune checkpoint blockade and adoptive T cell therapies. Their diverse characteristics can be reprogrammed by different immune challenges dependent on antigen stimulation levels, metabolic conditions, and the degree of inflammation. T cell-based therapeutic strategies are gaining widespread adoption in oncology and treating inflammatory conditions. Emerging researches reveal that clustered regularly interspaced palindromic repeats-associated protein 9 (CRISPR-Cas9) genome editing has enabled T cells to be more adaptable to specific microenvironments, opening the door to advanced T cell therapies in preclinical and clinical trials. CRISPR-Cas9 can edit both primary T cells and engineered T cells, including CAR-T and TCR-T, in vivo and in vitro to regulate T cell differentiation and activation states. This review first provides a comprehensive summary of the role of CRISPR-Cas9 in T cells and its applications in preclinical and clinical studies for T cell-based therapies. We also explore the application of CRISPR screen high-throughput technology in editing T cells and anticipate the current limitations of CRISPR-Cas9, including off-target effects and delivery challenges, and envisioned improvements in related technologies for disease screening, diagnosis, and treatment.


Assuntos
Sistemas CRISPR-Cas , Linfócitos T , Humanos , Sistemas CRISPR-Cas/genética , Diferenciação Celular , Inflamação , Ativação Linfocitária
5.
Immunity ; 57(4): 632-648, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38599163

RESUMO

One of the most significant conceptual advances in immunology in recent history is the recognition that signals from the innate immune system are required for induction of adaptive immune responses. Two breakthroughs were critical in establishing this paradigm: the identification of dendritic cells (DCs) as the cellular link between innate and adaptive immunity and the discovery of pattern recognition receptors (PRRs) as a molecular link that controls innate immune activation as well as DC function. Here, we recount the key events leading to these discoveries and discuss our current understanding of how PRRs shape adaptive immune responses, both indirectly through control of DC function and directly through control of lymphocyte function. In this context, we provide a conceptual framework for how variation in the signals generated by PRR activation, in DCs or other cell types, can influence T cell differentiation and shape the ensuing adaptive immune response.


Assuntos
Células Dendríticas , Imunidade Inata , Imunidade Adaptativa , Receptores de Reconhecimento de Padrão/metabolismo , Ativação Linfocitária
6.
J Exp Med ; 221(5)2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38557723

RESUMO

CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5-61 years from five families of four ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple's disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HLA class II, is affected by only one variant. All patients lack CD4+ T cells and have increased numbers of TCRαß+CD4-CD8- T cells, which phenotypically and transcriptionally resemble conventional Th cells. Finally, patient CD4-CD8- αß T cells exhibit intact responses to HLA class II-restricted antigens and promote B cell differentiation in vitro. Thus, compensatory development of Th cells enables patients with inherited CD4 deficiency to acquire effective cellular and humoral immunity against an unexpectedly large range of pathogens. Nevertheless, CD4 is indispensable for protective immunity against at least human papillomaviruses and Trophyrema whipplei.


Assuntos
Linfócitos T CD4-Positivos , Linfócitos T Auxiliares-Indutores , Humanos , Linfócitos T CD8-Positivos , Ativação Linfocitária , Antígenos HLA , Isoformas de Proteínas/metabolismo
7.
J Immunother Cancer ; 12(4)2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38580332

RESUMO

BACKGROUND: Regulatory T (Treg) cells are a key component in maintaining the suppressive tumor microenvironment and immune suppression in different types of cancers. A precise understanding of the molecular mechanisms used by Treg cells for immune suppression is critical for the development of effective strategies for cancer immunotherapy. METHODS: Senescence development and tolerogenic functions of dendritic cells (DCs) induced by breast cancer tumor-derived γδ Treg cells were fully characterized using real-time PCR, flow cytometry, western blot, and functional assays. Loss-of-function strategies with pharmacological inhibitor and/or neutralizing antibody were used to identify the potential molecule(s) and pathway(s) involved in DC senescence and dysfunction induced by Treg cells. Impaired tumor antigen HER2-specific recognition and immune response of senescent DCs induced by γδ Treg cells were explored in vitro and in vivo in humanized mouse models. In addition, the DC-based HER2 tumor vaccine immunotherapy in breast cancer models was performed to explore the enhanced antitumor immunity via prevention of DC senescence through blockages of STAT3 and programmed death-ligand 1 (PD-L1) signaling. RESULTS: We showed that tumor-derived γδ Treg cells promote the development of senescence in DCs with tolerogenic functions in breast cancer. Senescent DCs induced by γδ Treg cells suppress Th1 and Th17 cell differentiation but promote the development of Treg cells. In addition, we demonstrated that PD-L1 and STAT3 signaling pathways are critical and involved in senescence induction in DCs mediated by tumor-derived γδ Treg cells. Importantly, our complementary in vivo studies further demonstrated that blockages of PD-L1 and/or STAT3 signaling can prevent γδ Treg-induced senescence and reverse tolerogenic functions in DCs, resulting in enhanced HER2 tumor-specific immune responses and immunotherapy efficacy in human breast cancer models. CONCLUSIONS: These studies not only dissect the suppressive mechanism mediated by tumor-derived γδ Treg cells on DCs in the tumor microenvironment but also provide novel strategies to prevent senescence and dysfunction in DCs and enhance antitumor efficacy mediated by tumor-specific T cells for cancer immunotherapy.


Assuntos
Neoplasias da Mama , Linfócitos T Reguladores , Camundongos , Animais , Humanos , Feminino , Antígeno B7-H1/metabolismo , Imunoterapia , Ativação Linfocitária , Células Dendríticas , Microambiente Tumoral
8.
Medicine (Baltimore) ; 103(15): e37688, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38608099

RESUMO

Testicular germ cell tumors (TGCT) are the most common testicular malignancies. KLRB1 is considered to influence the development and progression of a number of cancers. However, it is unclear how the KLRB1 gene functions in TGCT. First, it was determined the expression level of KLRB1 in TGCT using The Cancer Genome Atlas (TCGA) (The Cancer Genome Atlas) dataset and GTEx (Genotype-Tissue Expression) dataset. The clinical significance and biological functions of KLRB1 were explored using the TCGA dataset, and we analyzed the correlation of the KLRB1 gene with tumor immunity and infiltrating immune cells using gene set variation analysis and the TIMER database. We found that the expression level of KLRB1 was upregulated in TGCT malignant tissues with the corresponding normal tissues as controls, and KLRB1 expression correlated with clinicopathologic features of TGCT. Functional enrichment analysis suggested that KLRB1 might be involved in immune response and inflammatory response. KLRB1 was highly positively correlated with natural killer cell activation in immune response and positively correlated with tumor-infiltrating immune cells. This study demonstrated for the first time the role of KLRB1 in TGCT, which may serve as a new biomarker associated with immune infiltration and provide a potential therapeutic target for the treatment of TGCT.


Assuntos
Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Humanos , Masculino , Neoplasias Testiculares/genética , Neoplasias Embrionárias de Células Germinativas/genética , Bases de Dados Factuais , Ativação Linfocitária , Subfamília B de Receptores Semelhantes a Lectina de Células NK
9.
Sci Immunol ; 9(93): eadn4958, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38489351

RESUMO

Upon lymphocyte stimulation, accumulation of intracellular NAD(H) reflects the strength of antigen receptor signals and controls the rate of cell cycle entry and proliferation (see related Research Article by Turner et al.).


Assuntos
Ativação Linfocitária , Corrida , Corrida/fisiologia
10.
J Immunother Cancer ; 12(3)2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38485289

RESUMO

BACKGROUND: While Programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) blockade is a potent antitumor treatment strategy, it is effective in only limited subsets of patients with cancer, emphasizing the need for the identification of additional immune checkpoints. Butyrophilin 1A1 (BTN1A1) has been reported to exhibit potential immunoregulatory activity, but its ability to function as an immune checkpoint remains to be systematically assessed, and the mechanisms underlying such activity have yet to be characterized. METHODS: BTN1A1 expression was evaluated in primary tumor tissue samples, and its ability to suppress T-cell activation and T cell-dependent tumor clearance was examined. The relationship between BTN1A1 and PD-L1 expression was further characterized, followed by the development of a BTN1A1-specific antibody that was administered to tumor-bearing mice to test the amenability of this target to immune checkpoint inhibition. RESULTS: BTN1A1 was confirmed to suppress T-cell activation in vitro and in vivo. Robust BTN1A1 expression was detected in a range of solid tumor tissue samples, and BTN1A1 expression was mutually exclusive with that of PD-L1 as a consequence of its inhibition of Janus-activated kinase/signal transducer and activator of transcription signaling-induced PD-L1 upregulation. Antibody-mediated BTN1A1 blockade suppressed tumor growth and enhanced immune cell infiltration in syngeneic tumor-bearing mice. CONCLUSION: Together, these results confirm that the potential of BTN1A1 is a bona fide immune checkpoint and a viable immunotherapeutic target for the treatment of individuals with anti-PD-1/PD-L1 refractory or resistant disease, opening new avenues to improving survival outcomes for patients with a range of cancers.


Assuntos
Antígeno B7-H1 , Neoplasias , Animais , Humanos , Camundongos , Butirofilinas , Ativação Linfocitária , Neoplasias/tratamento farmacológico , Linfócitos T , Regulação para Cima
11.
Cell Commun Signal ; 22(1): 169, 2024 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-38459508

RESUMO

Bach2 was initially discovered in B cells, where it was revealed to control the transcription involved in cell differentiation. Bach2 is intimately connected to CD8 + T lymphocytes in various differentiation states and subsets according to recent findings. Bach2 can regulate primitive T cells, stimulate the development and differentiation of memory CD8 + T cells, inhibit the differentiation of effector CD8 + T cells, and play a significant role in the exhaustion of CD8 + T cells. The appearance and development of diseases are tightly linked to irregular CD8 + T cell differentiation and function. Accordingly, Bach2 offers novel approaches and possible targets for the clinical treatment of associated disorders based on research on these pathways. Here, we summarize the role of Bach2 in the function and differentiation of CD8 + T cells and its potential clinical applications.


Assuntos
Linfócitos B , Linfócitos T CD8-Positivos , Diferenciação Celular , Ativação Linfocitária , Humanos
12.
J Am Chem Soc ; 146(11): 7233-7242, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38451498

RESUMO

The T cell membrane is studded with >104 T cell receptors (TCRs) that are used to scan target cells to identify short peptide fragments associated with viral infection or cancerous mutation. These peptides are presented as peptide-major-histocompatibility complexes (pMHCs) on the surface of virtually all nucleated cells. The TCR-pMHC complex forms at cell-cell junctions, is highly transient, and experiences mechanical forces. An important question in this area pertains to the role of the force duration in immune activation. Herein, we report the development of force probes that autonomously terminate tension within a time window following mechanical triggering. Force-induced site-specific enzymatic cleavage (FUSE) probes tune the tension duration by controlling the rate of a force-triggered endonuclease hydrolysis reaction. This new capability provides a method to study how the accumulated force duration contributes to T cell activation. We screened DNA sequences and identified FUSE probes that disrupt mechanical interactions with F > 7.1 piconewtons (pN) between TCRs and pMHCs. This rate of disruption, or force lifetime (τF), is tunable from tens of minutes down to 1.9 min. T cells challenged with FUSE probes with F > 7.1 pN presenting cognate antigens showed up to a 23% decrease in markers of early activation. FUSE probes with F > 17.0 pN showed weaker influence on T cell triggering further showing that TCR-pMHC with F > 17.0 pN are less frequent compared to F > 7.1 pN. Taken together, FUSE probes allow a new strategy to investigate the role of force dynamics in mechanotransduction broadly and specifically suggest a model of serial mechanical engagement boosting TCR activation.


Assuntos
Mecanotransdução Celular , Receptores de Antígenos de Linfócitos T , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T , Ativação Linfocitária , Fenômenos Mecânicos , Peptídeos/química , Ligação Proteica
13.
Vet Immunol Immunopathol ; 270: 110739, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38492410

RESUMO

The limited availability of canine-reactive monoclonal antibodies restricts the analyses of immune cell subsets and their functions by flow cytometry. The PrimeFlow™ RNA Assay may serve as a potential solution to close this gap. Here we report a blood immunophenotyping method utilizing combined protein- and RNA-based flow cytometry to characterize canine T cell activation and proliferation within individual cells. In this assay, CD69 expression was detected by an RNA probe and CD25 and Ki67 were detected by antibodies. Canine peripheral blood mononuclear cells (PBMCs) were stimulated with three agents with different modes of action, anti-CD3/CD28 antibodies, phytohemagglutinin, or phorbol myristate acetate /ionomycin. Robust T cell activation (CD25+ and/or CD69+) and proliferation (Ki67+) were detected. Both CD69 and CD25 appear to be robust and sensitive T cell activation markers with early induction and low background expression. Upon stimulation, T cell proliferation occurred later than T cell activation and was associated with CD25 expression. This canine T cell activation and proliferation immunophenotyping method was evaluated in 5 independent experiments using PBMCs from 10 different beagle dogs with satisfactory assay performance. This method can greatly facilitate the evaluation of immune disease pathogenesis and immunotoxicity risk assessment in nonclinical drug development in canine.


Assuntos
Antígenos CD , Leucócitos Mononucleares , Cães , Animais , RNA/metabolismo , Antígeno Ki-67 , Citometria de Fluxo/veterinária , Citometria de Fluxo/métodos , Imunofenotipagem/veterinária , Linfócitos T , Proliferação de Células , Ativação Linfocitária
14.
Int Immunopharmacol ; 131: 111821, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38484664

RESUMO

Chlamydia trachomatis (C.tr), an obligate intracellular pathogen, causes asymptomatic genital infections in women and is a leading cause of preventable blindness. We have developed in vivo mouse models of acute and chronic C. trachomatis genital infection to explore the significance of macrophage-directed response in mediating immune activation/suppression. Our findings reveal that during chronic and repeated C. trachomatis infections, Th1 response is abated while Treg response is enhanced. Additionally, an increase in exhaustion (PD1, CTLA4) and anergic (Klrg3, Tim3) T cell markers is observed during chronic infection. We have also observed that M2 macrophages with low CD40 expression promote Th2 and Treg differentiation leading to sustained C. trachomatis genital infection. Macrophages infected with C. trachomatis or treated with supernatant of infected epithelial cells drive them to an M2 phenotype. C. trachomatis infection prevents the increase in CD40 expression as observed in western blots and flow cytometric analysis. Insufficient IFNγ, as observed during chronic infection, leads to incomplete clearance of bacteria and poor immune activation. C. trachomatis decapacitates IFNγ responsiveness in macrophages via hampering IFNγRI and IFNγRII expression which can be correlated with poor expression of MHC-II, CD40, iNOS and NO release even following IFNγ supplementation. M2 macrophages during C. trachomatis infection express low CD40 rendering immunosuppressive, Th2 and Treg differentiation which could not be reverted even by IFNγ supplementation. The alternative macrophages also harbour high bacterial load and are poor responders to IFNγ, thus promoting immunosuppression. In summary, C. trachomatis modulates the innate immune cells, attenuating the anti-chlamydial functions of T cells in a manner that involves decreased CD40 expression on macrophages.


Assuntos
Antígenos CD40 , Infecções por Chlamydia , Chlamydia trachomatis , Interferon gama , Macrófagos , Animais , Feminino , Humanos , Camundongos , Antígenos CD40/metabolismo , Infecções por Chlamydia/imunologia , Infecções por Chlamydia/microbiologia , Chlamydia trachomatis/fisiologia , Células Epiteliais , Ativação Linfocitária , Macrófagos/metabolismo , Infecção Persistente , Interferon gama/imunologia , Interferon gama/metabolismo
15.
Fish Shellfish Immunol ; 148: 109482, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38458503

RESUMO

CD28 and CD80/86 are crucial co-stimulatory molecules for the T cell activation. Previous study illustrated that CD28 and CD80/86 present on T cells and antigen-presenting cells in flounder (Paralichthys olivaceus), respectively. The co-stimulatory molecules were closely associated with cell immunity. In this paper, recombinant protein of flounder CD80/86 (rCD80/86) and phytohemagglutinin (PHA) were added to peripheral blood leukocytes (PBLs) in vitro. Lymphocytes were significantly proliferated with CFSE staining, and the proportion of CD4+ and CD28+ lymphocytes significantly increased. In the meantime, genes related to the CD28-CD80/86 signaling pathway or T cell markers were significantly upregulated (p < 0.05). For further study, the interaction between CD80/86 and CD28 was confirmed. The plasmid of CD28 (pCD28-FLAG and pVN-CD28) or CD80/86 (pVC-CD80/86) was successfully constructed. In addition, pVN-ΔCD28 without the conserved motif "TFPPPF" was constructed. The results showed that bands of pCD28-FLAG bound to rCD80/86 were detected by both anti-FLAG and anti-CD80/86. pVN-CD28 complemented to pVC-CD80/86 showing positive fluorescent signals, and pVN-ΔCD28 failed to combine with pVC-CD80/86. The motif "TFPPPF" in CD28 played a crucial role in this linkage. These results indicate that CD28 and CD80/86 molecules interact with each other, and their binding may modulate T lymphocytes immune response in flounder. This study proved the existence of CD28-CD80/86 signaling pathway in flounder.


Assuntos
Antígenos CD28 , Linguado , Animais , Antígenos CD28/genética , Ativação Linfocitária , Antígeno B7-1/genética , Moléculas de Adesão Celular , Linfócitos T CD4-Positivos
16.
Fish Shellfish Immunol ; 148: 109515, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38499218

RESUMO

As a multipotent cytokine, interleukin (IL)-2 plays important roles in activation, differentiation and survival of the lymphocytes. Although biological characteristics and function of IL-2 have been clarified in several teleost species, evidence regarding IL-2 production at the cellular and protein levels is still scarce in fish due to the lack of reliable antibody. In this study, we developed a mouse anti-Nile tilapia IL-2 monoclonal antibody (mAb), which could specifically recognize IL-2 protein and identify IL-2-producing lymphocytes of tilapia. Using this mAb, we found that CD3+ T cells, but not CD3- lymphocytes, are the main cellular source of IL-2 in tilapia. Under resting condition, both CD3+CD4-1+ T cells and CD3+CD4-1- T cells of tilapia produce IL-2. Moreover, the IL-2 protein level and the frequency of IL-2+ T cells significantly increased once T cells were activated by phytohemagglutinin (PHA) or CD3 plus CD28 mAbs in vitro. In addition, Edwardsiella piscicida infection also induces the IL-2 production and the expansion of IL-2+ T cells in the spleen lymphocytes. These findings demonstrate that IL-2 takes part in the T-cell activation and anti-bacterial adaptive immune response of tilapia, and can serve as an important marker for T-cell activation of teleost fish. Our study has enriched the knowledge regarding T-cell response in fish species, and also provide novel perspective for understanding the evolution of adaptive immune system.


Assuntos
Antígenos CD28 , Interleucina-2 , Animais , Anticorpos Monoclonais , Complexo CD3 , Interleucina-2/genética , Ativação Linfocitária , Linfócitos T , Tilápia
17.
Trends Immunol ; 45(4): 234-236, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38521715

RESUMO

The role of antibody affinity in plasma cell (PC) differentiation from germinal centers (GCs) remains contested. Parallel studies by Sprumont et al. and Sutton and Gao et al. show that PCs emerging from GCs produce antibodies with a diverse range of affinities and lack signatures of affinity-based selection. Therefore, commitment to the PC lineage is affinity independent.


Assuntos
Linfócitos B , Centro Germinativo , Humanos , Ativação Linfocitária , Linhagem da Célula , Diferenciação Celular , Plasmócitos
18.
Sci Rep ; 14(1): 7066, 2024 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-38528023

RESUMO

Maintenance of genome integrity is instrumental in preventing cancer. In addition to DNA repair pathways that prevent damage to DNA, damage tolerance pathways allow for the survival of cells that encounter DNA damage during replication. The Rad6/18 pathway is instrumental in this process, mediating damage bypass by ubiquitination of proliferating cell nuclear antigen. Previous studies have shown different roles of Rad18 in vivo and in tumorigenesis. Here, we show that B cells induce Rad18 expression upon proliferation induction. We have therefore analysed the role of Rad18 in B cell activation as well as in B cell lymphomagenesis mediated by an Eµ-Myc transgene. We find no activation defects or survival differences between Rad18 WT mice and two different models of Rad18 deficient tumour mice. Also, tumour subtypes do not differ between the mouse models. Accordingly, functions of Rad18 in B cell activation and tumorigenesis may be compensated for by other pathways in B cells.


Assuntos
Ativação Linfocitária , Neoplasias , Ubiquitina-Proteína Ligases , Animais , Camundongos , Carcinogênese/genética , Dano ao DNA , Reparo do DNA , Replicação do DNA , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Proteínas de Ligação a DNA/metabolismo , Linfócitos B/metabolismo , Ativação Linfocitária/genética
19.
Methods Cell Biol ; 183: 355-380, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38548419

RESUMO

Tumor-draining lymph nodes (tumor-DLNs) provide a rich source of tumor-reactive lymphocytes which can be used in adoptive immunotherapy (AIT) and that circumvent the need to resect autologous tumor, without the challenges and shortcomings associated with using autologous tumor or anti-CD3 monoclonal antibody. Bryostatin/Ionomycin (Bryo/Io) provide a useful method of activating tumor-DLNs such that they can readily be expanded to sufficient numbers to be used in AIT, and growing the tumor-DLN lymphocytes in the gamma chain cytokines IL-7 plus IL-15 is superior to IL-2 in terms of T cell numbers and phenotype. AIT with these cells induces tumor regression and provides protection against metastases and future tumor challenge. Here, we provide a stepwise protocol to sensitize tumor-DLN cells in donor mice, activate tumor-DLN T cells ex vivo using Bryo/Io, expansion of these cells in gamma chain cytokines and adoptive transfer of the expanded cells back into tumor-bearing hosts. Methods relevant to these experiments, such as injecting tumor cells intravenously and monitoring for pulmonary metastases, tumor volume measurement and resection, and use of luciferase-expressing tumor cells to monitor for metastases following resection, are described in detail. The methods outlined herein can be easily adapted to suit similar experiments across multiple tumor cell lines and syngeneic mouse models.


Assuntos
Citocinas , Imunoterapia Adotiva , Camundongos , Animais , Imunoterapia Adotiva/métodos , Briostatinas , Ionomicina/farmacologia , Linfonodos , Ativação Linfocitária , Camundongos Endogâmicos C57BL
20.
Sci Immunol ; 9(93): eade6256, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38457513

RESUMO

Programmed cell death-1 (PD-1) is a potent immune checkpoint receptor on T lymphocytes. Upon engagement by its ligands, PD-L1 or PD-L2, PD-1 inhibits T cell activation and can promote immune tolerance. Antagonism of PD-1 signaling has proven effective in cancer immunotherapy, and conversely, agonists of the receptor may have a role in treating autoimmune disease. Some immune receptors function as dimers, but PD-1 has been considered monomeric. Here, we show that PD-1 and its ligands form dimers as a consequence of transmembrane domain interactions and that propensity for dimerization correlates with the ability of PD-1 to inhibit immune responses, antitumor immunity, cytotoxic T cell function, and autoimmune tissue destruction. These observations contribute to our understanding of the PD-1 axis and how it can potentially be manipulated for improved treatment of cancer and autoimmune diseases.


Assuntos
Doenças Autoimunes , Neoplasias , Humanos , Receptor de Morte Celular Programada 1 , Tolerância Imunológica , Ativação Linfocitária , Domínios Proteicos
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