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Frontiers in Immunology 2023The mature lymphocyte population of a healthy individual has the remarkable ability to recognise an immense variety of antigens. Instead of encoding a unique gene for... (Review)
Review
The mature lymphocyte population of a healthy individual has the remarkable ability to recognise an immense variety of antigens. Instead of encoding a unique gene for each potential antigen receptor, evolution has used gene rearrangements, also known as variable, diversity, and joining gene segment (V(D)J) recombination. This process is critical for lymphocyte development and relies on recombination-activating genes-1 (RAG1) and RAG2, here collectively referred to as RAG. RAG serves as powerful genome editing tools for lymphocytes and is strictly regulated to prevent dysregulation. However, in the case of dysregulation, RAG has been implicated in cases of cancer, autoimmunity and severe combined immunodeficiency (SCID). This review examines functional protein domains and motifs of RAG, describes advances in our understanding of the function and (dys)regulation of RAG, discuss new therapeutic options, such as gene therapy, for RAG deficiencies, and explore and methods for determining RAG activity and target specificity.
Topics: Homeodomain Proteins; Recombinases; Gene Rearrangement; Lymphocytes; Genes, RAG-1
PubMed: 37497222
DOI: 10.3389/fimmu.2023.1210818 -
Frontiers in Immunology 2023Cytotoxic lymphocytes kill target cells through polarized release of the content of cytotoxic granules towards the target cell. The importance of this cytotoxic pathway... (Review)
Review
Cytotoxic lymphocytes kill target cells through polarized release of the content of cytotoxic granules towards the target cell. The importance of this cytotoxic pathway in immune regulation is evidenced by the severe and often fatal condition, known as hemophagocytic lymphohistiocytosis (HLH) that occurs in mice and humans with inborn errors of lymphocyte cytotoxic function. The clinical and preclinical data indicate that the damage seen in severe, virally triggered HLH is due to an overwhelming immune system reaction and not the direct effects of the virus . The main HLH-disease mechanism, which links impaired cytotoxicity to excessive release of pro-inflammatory cytokines is a prolongation of the synapse time between the cytotoxic effector cell and the target cell, which prompts the former to secrete larger amounts of cytokines (including interferon gamma) that activate macrophages. We and others have identified novel genetic HLH spectrum disorders. In the present update, we position these newly reported molecular causes, including CD48-haploinsufficiency and ZNFX1-deficiency, within the pathogenic pathways that lead to HLH. These genetic defects have consequences on the cellular level on a gradient model ranging from impaired lymphocyte cytotoxicity to intrinsic activation of macrophages and virally infected cells. Altogether, it is clear that target cells and macrophages may play an independent role and are not passive bystanders in the pathogenesis of HLH. Understanding these processes which lead to immune dysregulation may pave the way to novel ideas for medical intervention in HLH and virally triggered hypercytokinemia.
Topics: Humans; Animals; Mice; Cytokines; Lymphohistiocytosis, Hemophagocytic; Lymphocytes; Cytotoxicity, Immunologic; Interferon-gamma
PubMed: 37187762
DOI: 10.3389/fimmu.2023.1163316 -
Frontiers in Immunology 2018
Topics: Allergy and Immunology; Biomedical Research; Cytokines; Graft vs Host Disease; History, 20th Century; History, 21st Century; Humans; Lymphocytes; Male; Research Personnel
PubMed: 30619279
DOI: 10.3389/fimmu.2018.02915 -
Journal of Clinical Immunology Aug 2023A subset of common variable immunodeficiency (CVID) patients either presents with or develops autoimmune and lymphoproliferative complications, such as granulomatous...
PURPOSE
A subset of common variable immunodeficiency (CVID) patients either presents with or develops autoimmune and lymphoproliferative complications, such as granulomatous lymphocytic interstitial lung disease (GLILD), a major cause of morbidity and mortality in CVID. While a myriad of phenotypic lymphocyte derangements has been associated with and described in GLILD, defects in T and B cell antigen receptor (TCR/BCR) signaling in CVID and CVID with GLILD (CVID/GLILD) remain undefined, hindering discovery of biomarkers for disease monitoring, prognostic prediction, and personalized medicine approaches.
METHODS
To identify perturbations of immune cell subsets and TCR/BCR signal transduction, we applied mass cytometry analysis to peripheral blood mononuclear cells (PBMCs) from healthy control participants (HC), CVID, and CVID/GLILD patients.
RESULTS
Patients with CVID, regardless of GLILD status, had increased frequency of HLADRCD4 T cells, CD57CD8 T cells, and CD21 B cells when compared to healthy controls. Within these cellular populations in CVID/GLILD patients only, engagement of T or B cell antigen receptors resulted in discordant downstream signaling responses compared to CVID. In CVID/GLILD patients, CD21 B cells showed perturbed BCR-mediated phospholipase C gamma and extracellular signal-regulated kinase activation, while HLADRCD4 T cells and CD57CD8 T cells displayed disrupted TCR-mediated activation of kinases most proximal to the receptor.
CONCLUSION
Both CVID and CVID/GLILD patients demonstrate an activated T and B cell phenotype compared to HC. However, only CVID/GLILD patients exhibit altered TCR/BCR signaling in the activated lymphocyte subsets. These findings contribute to our understanding of the mechanisms of immune dysregulation in CVID with GLILD.
Topics: Humans; Lung Diseases, Interstitial; Common Variable Immunodeficiency; CD8-Positive T-Lymphocytes; Leukocytes, Mononuclear; Lymphocytes; Signal Transduction; Receptors, Antigen, B-Cell; Receptors, Antigen, T-Cell
PubMed: 37093407
DOI: 10.1007/s10875-023-01485-9 -
Current Opinion in Immunology Dec 2023The proper functioning of cytotoxic lymphocytes, such as natural killer and CD8+ T cells, is essential for effective cancer-immunity and immunotherapy responses. The... (Review)
Review
The proper functioning of cytotoxic lymphocytes, such as natural killer and CD8+ T cells, is essential for effective cancer-immunity and immunotherapy responses. The differentiation of these cells is controlled by several transcription factors (TFs), including members of the activator protein (AP)-1 family. The activity of AP-1 family members is regulated by various immune signaling pathways, which can be triggered by activating or inhibitory receptors as well as cytokines. The target genes controlled by AP-1 TFs are central to generate immunity to pathogens or malignancies. Here, we provide an overview of the current understanding of how AP-1 TFs regulate cytotoxic lymphocytes.
Topics: Humans; Transcription Factor AP-1; CD8-Positive T-Lymphocytes; Antineoplastic Agents; Neoplasms; Cytokines; T-Lymphocytes, Cytotoxic
PubMed: 37931499
DOI: 10.1016/j.coi.2023.102397 -
Seminars in Immunopathology Jan 2017The development of T helper cell subsets requires activated T cells that respond to a polarizing cytokine environment resulting in the activation and expression of... (Review)
Review
The development of T helper cell subsets requires activated T cells that respond to a polarizing cytokine environment resulting in the activation and expression of transcription factors. The subset-specific transcription factors bind and induce the production of specific effector cytokines. Th9 cells express IL-9 and develop in the presence of TGFβ, IL-4, and IL-2. Each of these cytokines activates signaling pathways that are required for Th9 differentiation and IL-9 production. In this review, I summarize what is currently understood about the signaling pathways and transcription factors that promote the Th9 genetic program, providing some perspective for the integration of the signals in regulating the Il9 gene and dictating the expression of other Th9-associated genes. I highlight how experiments in mouse cells have established a transcriptional network that is conserved in human T cells and set the stage toward defining the next important questions for a more detailed understanding of Th9 cell development and function.
Topics: Animals; Cell Differentiation; Cytokines; Gene Expression Regulation; Humans; Interleukin-9; Phenotype; Protein Binding; Protein Interaction Maps; Receptors, Antigen, T-Cell; Regulatory Sequences, Nucleic Acid; Signal Transduction; T-Lymphocyte Subsets; T-Lymphocytes, Helper-Inducer; Transcription Factors; Transcription, Genetic
PubMed: 27837254
DOI: 10.1007/s00281-016-0600-2 -
Cancer Research Communications Sep 2022CD19-redirected chimeric antigen receptor (CAR) T cells have shown remarkable activity against B-cell cancers. While second-generation CARs induce complete remission in...
UNLABELLED
CD19-redirected chimeric antigen receptor (CAR) T cells have shown remarkable activity against B-cell cancers. While second-generation CARs induce complete remission in >80% of patients with acute lymphoblastic leukemia, similar monotherapy induces long-term remissions in only 26% of patients with chronic lymphocytic leukemia (CLL). This disparity is attributed to cell-intrinsic effector defects in autologous CLL-derived T cells. However, the mechanisms by which leukemic cells impact CAR T-cell potency are poorly understood. Herein we describe an assay that recapitulates endogenous CLL-mediated T-cell defects in healthy donor CAR T cells. Contact with CLL cells insufficiently activates, but does not irreversibly impair, CAR T-cell function. This state is rescuable by strong antigenic stimulation or IL2, and is not driven by immune suppression. Rather, this activation defect is attributable to low levels of costimulatory molecules on CLL cells, and exogenous costimulation enhanced CAR T-cell activation. We next assessed the stimulatory phenotype of CLL cells derived from different niches within the same patient. Lymph node (LN)-derived CLL cells had a strong costimulatory phenotype and promoted better CAR T-cell degranulation and cytokine production than matched peripheral blood CLL cells. Finally, CD40L-activated CLL cells acquired a costimulatory phenotype similar to the LN-derived tumor and stimulated improved CAR T-cell proliferation, cytokine production, and cytotoxicity. Together, these data identify insufficient activation as a driver of poor CAR T-cell responses in CLL. The costimulatory phenotype of CLL cells drives differential CAR T-cell responses, and can be augmented by improving costimulatory signaling.
SIGNIFICANCE
CLL cells insufficiently activate CAR T cells, driven by low levels of costimulatory molecules on the tumor. LN-derived CLL cells are more costimulatory and mediate enhanced CAR T-cell killing. This costimulatory phenotype can be modeled via CD40 L activation, and the activated tumor promotes stronger CAR T-cell responses.
Topics: Humans; T-Lymphocytes; Leukemia, Lymphocytic, Chronic, B-Cell; Receptors, Chimeric Antigen; B-Lymphocytes; CD40 Ligand
PubMed: 36922932
DOI: 10.1158/2767-9764.CRC-22-0200 -
Nature Communications Jun 2023Agents that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represent promising approaches for HIV...
Agents that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represent promising approaches for HIV cure. Here, we develop and evaluate a trispecific antibody (Ab), N6/αCD3-αCD28, that targets three independent proteins: (1) the HIV envelope via the broadly reactive CD4-binding site Ab, N6; (2) the T cell antigen CD3; and (3) the co-stimulatory molecule CD28. We find that the trispecific significantly increases antigen-specific T-cell activation and cytokine release in both CD4 and CD8 T cells. Co-culturing CD4 with autologous CD8 T cells from ART-suppressed HIV donors with N6/αCD3-αCD28, results in activation of latently-infected cells and their elimination by activated CD8 T cells. This trispecific antibody mediates CD4 and CD8 T-cell activation in non-human primates and is well tolerated in vivo. This HIV-directed antibody therefore merits further development as a potential intervention for the eradication of latent HIV infection.
Topics: Animals; HIV Infections; CD8-Positive T-Lymphocytes; HIV-1; CD4-Positive T-Lymphocytes; Virus Latency; HIV Antibodies
PubMed: 37349337
DOI: 10.1038/s41467-023-39265-z -
Annals of Allergy, Asthma & Immunology... Feb 2021Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a chronic type 2 inflammatory response in the paranasal sinuses. Group 2 innate lymphoid cells... (Review)
Review
OBJECTIVE
Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a chronic type 2 inflammatory response in the paranasal sinuses. Group 2 innate lymphoid cells (ILC2s) are potent innate immune cells that contribute to type 2 inflammation by producing cytokines such as interleukin (IL)-4, IL-5, and IL-13. There is increasing evidence suggesting that ILC2s play an important role in the CRSwNP pathogenesis.
DATA SOURCES
We reviewed published literature obtained through PubMed inquiries.
STUDY SELECTIONS
Studies relevant to the presence, function, and activation of ILC2s in CRSwNP were included.
RESULTS
Nasal polyps (NPs) are one of the first tissues in which human ILC2s were discovered, and many groups have since reported that these cells are highly elevated in NPs. ILC2s in NPs are also highly activated and produce type 2 cytokines in vivo. Mediators known to activate ILC2s, including receptor activator of nuclear factor kappa-Β ligand, thymic stromal lymphopoietin, various lipid mediators (including prostaglandin D and cysteinyl leukotrienes), IL-4, and IL-13 have also been shown to be elevated in NPs compared with healthy sinonasal tissue. Other well-known ILC2 activators, IL-25 and IL-33, are sometimes elevated in NPs in some countries. Furthermore, activation of ILC2s by means of 4 distinct transcriptional pathways (nuclear factor kappa-light-chain-enhancer of activated B cells, nuclear factor of activated T cells, signal transducer and activator of transcription 5, and signal transducer and activator of transcription 6) is needed for the most robust generation of type 2 cytokines.
CONCLUSION
ILC2-mediated type 2 inflammation plays a crucial role in the pathogenesis of CRSwNP. Targeting the upstream mediators responsible for activating ILC2s and the downstream products that these cells release may play an important role in modifying the inflammatory response and improving clinical outcomes in CRSwNP.
Topics: Animals; Asthma, Aspirin-Induced; Chronic Disease; Humans; Immunity, Innate; Lymphocytes; Nasal Polyps; Rhinitis; Sinusitis
PubMed: 32781240
DOI: 10.1016/j.anai.2020.08.001 -
European Journal of Cell Biology 2022tT cells migrate to lymphoid organs to become activated through specific contacts with antigen-presenting cells bearing foreign antigens. During migration and... (Review)
Review
tT cells migrate to lymphoid organs to become activated through specific contacts with antigen-presenting cells bearing foreign antigens. During migration and activation, T lymphocytes are exposed not only to diverse biochemical inputs, but also to different mechanical conditions. Passage from the blood or lymph to solid tissues involves lymphocyte rolling, firm arrest and diapedesis through endothelial monolayers. Throughout this process, cells are subjected to diverse fluid flow regimes. After extravasation, T lymphocytes crawl through viscoelastic media of different biochemical and mechanical properties and geometries. In lymph nodes, T cell contact with antigen-presenting cells is guided by rigidity cues and ligand-receptor interactions. T lymphocyte adaptation to diverse mechanical regimes involves multiple signaling and morphological modifications, many of which enable the conversion of mechanical forces into biochemical signals and vice-versa. These components enable T lymphocyte survival, homing and activation. Here, we review the mechanisms that enable T lymphocytes to survive and thrive under the different mechanical conditions they encounter during their life cycle. These processes require the integration of diverse signaling networks that convert extracellular mechano-chemical cues into force, movement and activation.
Topics: Cell Movement; Lymphocytes; Signal Transduction; T-Lymphocytes
PubMed: 35588542
DOI: 10.1016/j.ejcb.2022.151236