المؤلفون: Rutishauser, Rachel L, Deguit, Christian Deo T, Hiatt, Joseph, Blaeschke, Franziska, Roth, Theodore L, Wang, Lynn, Raymond, Kyle A, Starke, Carly E, Mudd, Joseph C, Chen, Wenxuan, Smullin, Carolyn P, Matus-Nicodemos, Rodrigo, Hoh, Rebecca, Krone, Melissa R, Hecht, Frederick M, Pilcher, Christopher D, Martin, Jeffrey N, Koup, Richard A, Douek, Daniel C, Brenchley, Jason M, Sékaly, Rafick-Pierre, Pillai, Satish K, Marson, Alexander, Deeks, Steven G, McCune, Joseph M, Hunt, Peter W

المصدر: JCI Insight. 6(3)

مصطلحات موضوعية: Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Sexually Transmitted Infections, HIV/AIDS, Infectious Diseases, Underpinning research, 1.1 Normal biological development and functioning, Infection, Good Health and Well Being, Adult, Aged, Animals, CD8-Positive T-Lymphocytes, Female, Gene Knockout Techniques, HIV Antigens, HIV Infections, HIV-1, Humans, Immunologic Memory, Macaca mulatta, Male, Middle Aged, Simian Acquired Immunodeficiency Syndrome, Simian Immunodeficiency Virus, T Cell Transcription Factor 1, Viral Load, Simian immunodeficiency virus, AIDS/HIV, Adaptive immunity, T cells, Biomedical and clinical sciences, Health sciences

الوصف: Although many HIV cure strategies seek to expand HIV-specific CD8+ T cells to control the virus, all are likely to fail if cellular exhaustion is not prevented. A loss in stem-like memory properties (i.e., the ability to proliferate and generate secondary effector cells) is a key feature of exhaustion; little is known, however, about how these properties are regulated in human virus-specific CD8+ T cells. We found that virus-specific CD8+ T cells from humans and nonhuman primates naturally controlling HIV/SIV infection express more of the transcription factor TCF-1 than noncontrollers. HIV-specific CD8+ T cell TCF-1 expression correlated with memory marker expression and expansion capacity and declined with antigenic stimulation. CRISPR-Cas9 editing of TCF-1 in human primary T cells demonstrated a direct role in regulating expansion capacity. Collectively, these data suggest that TCF-1 contributes to the regulation of the stem-like memory property of secondary expansion capacity of HIV-specific CD8+ T cells, and they provide a rationale for exploring the enhancement of this pathway in T cell-based therapeutic strategies for HIV.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/9hs4z0n1Test
https://escholarship.org/content/qt9hs4z0n1/qt9hs4z0n1.pdfTest

المؤلفون: Herold, Kevan C, Bucktrout, Samantha L, Wang, Xiao, Bode, Bruce W, Gitelman, Stephen E, Gottlieb, Peter A, Hughes, Jing, Joh, Tenshang, McGill, Janet B, Pettus, Jeremy H, Potluri, Shobha, Schatz, Desmond, Shannon, Megan, Udata, Chandrasekhar, Wong, Gilbert, Levisetti, Matteo, Ganguly, Bishu J, Garzone, Pamela D

المصدر: JCI Insight. 4(24)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Immunology, Clinical Trials and Supportive Activities, Diabetes, Autoimmune Disease, Immunization, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Inflammatory and immune system, Adult, Antibodies, Monoclonal, Humanized, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Survival, Diabetes Mellitus, Type 1, Dose-Response Relationship, Drug, Dose-Response Relationship, Immunologic, Female, Humans, Immunologic Memory, Interleukin-7, Interleukin-7 Receptor alpha Subunit, Male, Middle Aged, Signal Transduction, Treatment Outcome, RN168 Working Group, Clinical Trials, T cells, Biomedical and clinical sciences, Health sciences

الوصف: The cytokine IL-7 is critical for T cell development and function. We performed a Phase Ib study in patients with type 1 diabetes (T1D) to evaluate how blockade of IL-7 would affect immune cells and relevant clinical responses. Thirty-seven subjects with T1D received s.c. RN168, a monoclonal antibody that blocks the IL -7 receptor α (IL7Rα) in a dose-escalating study. Between 90% and 100% IL-7R occupancy and near-complete inhibition of pSTAT5 was observed at doses of RN168 1 mg/kg every other week (Q2wk) and greater. There was a significant decline in CD4+ and CD8+ effector and central memory T cells and CD4+ naive cells, but there were fewer effects on CD8+ naive T cells. The ratios of Tregs to CD4+ or CD8+ effector and central memory T cells versus baseline were increased. RNA sequencing analysis showed downmodulation of genes associated with activation, survival, and differentiation of T cells. Expression of the antiapoptotic protein Bcl-2 was reduced. The majority of treatment-emergent adverse events (TEAEs) were mild and not treatment related. Four subjects became anti-EBV IgG+ after RN168, and 2 had symptoms of active infection. The immunologic response to tetanus toxoid was preserved at doses of 1 and 3 mg/kg Q2wk but reduced at higher doses. This trial shows that, at dosages of 1-3 mg/kg, RN168 selectively inhibits the survival and activity of memory T cells while preserving naive T cells and Tregs. These immunologic effects may serve to eliminate pathologic T cells in autoimmune diseases. NCT02038764. Pfizer Inc.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8q17347qTest

المؤلفون: Bocharnikov, Alexandra V, Keegan, Joshua, Wacleche, Vanessa S, Cao, Ye, Fonseka, Chamith Y, Wang, Guoxing, Muise, Eric S, Zhang, Kelvin X, Arazi, Arnon, Keras, Gregory, Li, Zhihan J, Qu, Yujie, Gurish, Michael F, Petri, Michelle, Buyon, Jill P, Putterman, Chaim, Wofsy, David, James, Judith A, Guthridge, Joel M, Diamond, Betty, Anolik, Jennifer H, Mackey, Matthew F, Alves, Stephen E, Nigrovic, Peter A, Costenbader, Karen H, Brenner, Michael B, Lederer, James A, Rao, Deepak A

المصدر: JCI Insight. 4(20)

مصطلحات موضوعية: Lupus, Kidney Disease, Autoimmune Disease, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Adult, Aged, B-Lymphocytes, CD11c Antigen, CRISPR-Cas Systems, Case-Control Studies, Cell Communication, Cell Culture Techniques, Cell Separation, Cells, Cultured, Coculture Techniques, Female, Flow Cytometry, Gene Knockout Techniques, Humans, Interleukins, Lupus Erythematosus, Systemic, Lymphocyte Activation, Male, Middle Aged, Programmed Cell Death 1 Receptor, Proto-Oncogene Proteins c-maf, RNA-Seq, Receptors, CXCR5, T-Lymphocytes, Helper-Inducer, Accelerating Medicines Partnership (AMP) RA/SLE Network, Adaptive immunity, Autoimmunity, Immunology, T cells

الوصف: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathologic T cell-B cell interactions and autoantibody production. Defining the T cell populations that drive B cell responses in SLE may enable design of therapies that specifically target pathologic cell subsets. Here, we evaluated the phenotypes of CD4+ T cells in the circulation of 52 SLE patients drawn from multiple cohorts and identified a highly expanded PD-1hiCXCR5-CD4+ T cell population. Cytometric, transcriptomic, and functional assays demonstrated that PD-1hiCXCR5-CD4+ T cells from SLE patients are T peripheral helper (Tph) cells, a CXCR5- T cell population that stimulates B cell responses via IL-21. The frequency of Tph cells, but not T follicular helper (Tfh) cells, correlated with both clinical disease activity and the frequency of CD11c+ B cells in SLE patients. PD-1hiCD4+ T cells were found within lupus nephritis kidneys and correlated with B cell numbers in the kidney. Both IL-21 neutralization and CRISPR-mediated deletion of MAF abrogated the ability of Tph cells to induce memory B cell differentiation into plasmablasts in vitro. These findings identify Tph cells as a highly expanded T cell population in SLE and suggest a key role for Tph cells in stimulating pathologic B cell responses.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/7jh3p8qhTest

المؤلفون: Hacken, Elisa ten, Valentin, Rebecca, Regis, Fara Faye D, Sun, Jing, Yin, Shanye, Werner, Lillian, Deng, Jing, Gruber, Michaela, Wong, Jessica, Zheng, Mei, Gill, Amy L, Seiler, Michael, Smith, Peter, Thomas, Michael, Buonamici, Silvia, Ghia, Emanuela M, Kim, Ekaterina, Rassenti, Laura Z, Burger, Jan A, Kipps, Thomas J, Meyerson, Matthew L, Bachireddy, Pavan, Wang, Lili, Reed, Robin, Neuberg, Donna, Carrasco, Ruben D, Brooks, Angela N, Letai, Anthony, Davids, Matthew S, Wu, Catherine J

المصدر: JCI Insight. 3(19)

مصطلحات موضوعية: Hematology, Genetics, Cancer, Rare Diseases, Orphan Drug, Clinical Research, Lymphoma, Adult, Aged, Aged, 80 and over, Alternative Splicing, Animals, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Bridged Bicyclo Compounds, Heterocyclic, Disease Models, Animal, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Epoxy Compounds, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Macrolides, Male, Mice, Mice, Transgenic, Middle Aged, Mitochondria, Mutation, Myeloid Cell Leukemia Sequence 1 Protein, Phosphoproteins, Primary Cell Culture, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Pyrimidines, RNA Splicing Factors, Spliceosomes, Sulfonamides, Thiophenes, Apoptosis inhibitors, Therapeutics, Transcription

الوصف: The identification of targetable vulnerabilities in the context of therapeutic resistance is a key challenge in cancer treatment. We detected pervasive aberrant splicing as a characteristic feature of chronic lymphocytic leukemia (CLL), irrespective of splicing factor mutation status, which was associated with sensitivity to the spliceosome modulator, E7107. Splicing modulation affected CLL survival pathways, including members of the B cell lymphoma-2 (BCL2) family of proteins, remodeling antiapoptotic dependencies of human and murine CLL cells. E7107 treatment decreased myeloid cell leukemia-1 (MCL1) dependence and increased BCL2 dependence, sensitizing primary human CLL cells and venetoclax-resistant CLL-like cells from an Eμ-TCL1-based adoptive transfer murine model to treatment with the BCL2 inhibitor venetoclax. Our data provide preclinical rationale to support the combination of venetoclax with splicing modulators to reprogram apoptotic dependencies in CLL for treating venetoclax-resistant CLL cases.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/70g3v1fmTest

المؤلفون: Chen, Pin-I, Cao, Aiqin, Miyagawa, Kazuya, Tojais, Nancy F, Hennigs, Jan K, Li, Caiyun G, Sweeney, Nathaly M, Inglis, Audrey S, Wang, Lingli, Li, Dan, Ye, Matthew, Feldman, Brian J, Rabinovitch, Marlene

المصدر: JCI Insight. 2(2)

مصطلحات موضوعية: Rare Diseases, Substance Misuse, Lung, Genetics, Methamphetamine, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Good Health and Well Being, Adult, Amphetamine-Related Disorders, Amphetamines, Animals, Caspase 3, DNA Damage, Electron Transport, Endothelial Cells, Female, Humans, Hypertension, Pulmonary, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, In Vitro Techniques, Male, Mice, Middle Aged, Mitochondria, Oxidative Phosphorylation, Protein Phosphatase 2, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, Pulmonary Artery, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Reactive Oxygen Species, Sirtuin 1, Vascular Remodeling, Cell Biology, Vascular Biology

الوصف: Amphetamine (AMPH) or methamphetamine (METH) abuse can cause oxidative damage and is a risk factor for diseases including pulmonary arterial hypertension (PAH). Pulmonary artery endothelial cells (PAECs) from AMPH-associated-PAH patients show DNA damage as judged by γH2AX foci and DNA comet tails. We therefore hypothesized that AMPH induces DNA damage and vascular pathology by interfering with normal adaptation to an environmental perturbation causing oxidative stress. Consistent with this, we found that AMPH alone does not cause DNA damage in normoxic PAECs, but greatly amplifies DNA damage in hypoxic PAECs. The mechanism involves AMPH activation of protein phosphatase 2A, which potentiates inhibition of Akt. This increases sirtuin 1, causing deacetylation and degradation of HIF1α, thereby impairing its transcriptional activity, resulting in a reduction in pyruvate dehydrogenase kinase 1 and impaired cytochrome c oxidase 4 isoform switch. Mitochondrial oxidative phosphorylation is inappropriately enhanced and, as a result of impaired electron transport and mitochondrial ROS increase, caspase-3 is activated and DNA damage is induced. In mice given binge doses of METH followed by hypoxia, HIF1α is suppressed and pulmonary artery DNA damage foci are associated with worse pulmonary vascular remodeling. Thus, chronic AMPH/METH can induce DNA damage associated with vascular disease by subverting the adaptive responses to oxidative stress.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/9g5942r4Test

المؤلفون: Moschos, Stergios J, Sullivan, Ryan J, Hwu, Wen-Jen, Ramanathan, Ramesh K, Adjei, Alex A, Fong, Peter C, Shapira-Frommer, Ronnie, Tawbi, Hussein A, Rubino, Joseph, Rush, Thomas S, Zhang, Da, Miselis, Nathan R, Samatar, Ahmed A, Chun, Patrick, Rubin, Eric H, Schiller, James, Long, Brian J, Dayananth, Priya, Carr, Donna, Kirschmeier, Paul, Bishop, W Robert, Deng, Yongqi, Cooper, Alan, Shipps, Gerald W, Moreno, Blanca Homet, Robert, Lidia, Ribas, Antoni, Flaherty, Keith T

المصدر: JCI Insight. 3(4)

مصطلحات موضوعية: Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Cancer, Clinical Trials and Supportive Activities, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Administration, Oral, Adult, Animals, Biological Availability, Cell Line, Tumor, Diarrhea, Dogs, Dose-Response Relationship, Drug, Drug Eruptions, Drug Evaluation, Preclinical, Fatigue, Female, Humans, Indazoles, MAP Kinase Signaling System, Male, Maximum Tolerated Dose, Mice, Middle Aged, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Nausea, Neoplasm Staging, Neoplasms, Protein Kinase Inhibitors, Pyridines, Pyrrolidines, Rats, Triazoles, Xenograft Model Antitumor Assays, Young Adult, Clinical Trials, Melanoma, Oncology, Signal transduction, Biomedical and clinical sciences, Health sciences

الوصف: BackgroundConstitutive activation of ERK1/2 occurs in various cancers, and its reactivation is a well-described resistance mechanism to MAPK inhibitors. ERK inhibitors may overcome the limitations of MAPK inhibitor blockade. The dual mechanism inhibitor SCH772984 has shown promising preclinical activity across various BRAFV600/RAS-mutant cancer cell lines and human cancer xenografts.MethodsWe have developed an orally bioavailable ERK inhibitor, MK-8353; conducted preclinical studies to demonstrate activity, pharmacodynamic endpoints, dosing, and schedule; completed a study in healthy volunteers (P07652); and subsequently performed a phase I clinical trial in patients with advanced solid tumors (MK-8353-001). In the P07652 study, MK-8353 was administered as a single dose in 10- to 400-mg dose cohorts, whereas in the MK-8353-001 study, MK-8353 was administered in 100- to 800-mg dose cohorts orally twice daily. Safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity were analyzed.ResultsMK-8353 exhibited comparable potency with SCH772984 across various preclinical cancer models. Forty-eight patients were enrolled in the P07652 study, and twenty-six patients were enrolled in the MK-8353-001 study. Adverse events included diarrhea (44%), fatigue (40%), nausea (32%), and rash (28%). Dose-limiting toxicity was observed in the 400-mg and 800-mg dose cohorts. Sufficient exposure to MK-8353 was noted that correlated with biological activity in preclinical data. Three of fifteen patients evaluable for treatment response in the MK-8353-001 study had partial response, all with BRAFV600-mutant melanomas.ConclusionMK-8353 was well tolerated up to 400 mg twice daily and exhibited antitumor activity in patients with BRAFV600-mutant melanoma. However, antitumor activity was not particularly correlated with pharmacodynamic parameters.Trial registrationClinicalTrials.gov NCT01358331.FundingMerck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., and NIH (P01 CA168585 and R35 CA197633).

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/9552v98dTest

المؤلفون: Lai Yee Cheong, Ruby L. C. Hoo, Xiaoyu Xiao, Yang Liu, Yang Xiao, Zhiguang Zhou, Boya Liao, Aimin Xu, Xiaoping Wu, Lingling Shu

المصدر: JCI Insight, Vol 6, Iss 7 (2021)
JCI Insight

مصطلحات موضوعية: 0301 basic medicine, Adult, Male, Adoptive cell transfer, T-Lymphocytes, Autoimmunity, medicine.disease_cause, Fatty Acid-Binding Proteins, Diabetes Mellitus, Experimental, 03 medical and health sciences, Islets of Langerhans, 0302 clinical medicine, Immune system, Endocrinology, Mice, Inbred NOD, Medicine, Animals, Humans, Benzothiazoles, NOD mice, Autoantibodies, Bone Marrow Transplantation, Innate immunity, Type 1 diabetes, geography, geography.geographical_feature_category, Innate immune system, business.industry, Macrophages, Diabetes, Autoantibody, General Medicine, Carbocyanines, Middle Aged, medicine.disease, Islet, Mice, Mutant Strains, 030104 developmental biology, Diabetes Mellitus, Type 1, 030220 oncology & carcinogenesis, Immunology, Female, business, Research Article

الوصف: Both innate and adaptive immune cells are critical players in autoimmune destruction of insulin-producing β cells in type 1 diabetes. However, the early pathogenic events triggering the recruitment and activation of innate immune cells in islets remain obscure. Here we show that circulating fatty acid binding protein 4 (FABP4) level was significantly elevated in patients with type 1 diabetes and their first-degree relatives and positively correlated with the titers of several islet autoantibodies. In nonobese diabetic (NOD) mice, increased FABP4 expression in islet macrophages started from the neonatal period, well before the occurrence of overt diabetes. Furthermore, the spontaneous development of autoimmune diabetes in NOD mice was markedly reduced by pharmacological inhibition or genetic ablation of FABP4 or adoptive transfer of FABP4-deficient bone marrow cells. Mechanistically, FABP4 activated innate immune responses in islets by enhancing the infiltration and polarization of macrophages to proinflammatory M1 subtype, thus creating an inflammatory milieu required for activation of diabetogenic CD8+ T cells and shift of CD4+ helper T cells toward Th1 subtypes. These findings demonstrate FABP4 as a possible early mediator for β cell autoimmunity by facilitating crosstalk between innate and adaptive immune cells, suggesting that pharmacological inhibition of FABP4 may represent a promising therapeutic strategy for autoimmune diabetes.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b49e44f810f16457012d14ea324cf550Test
https://doaj.org/article/4cae76f959a34aa7a137d440a57963ccTest

المؤلفون: John D. Port, Tiffany Cortes, Gregory N. Ruegsegger, Ana L. Creo, Andrea R.S. Huebner, Yogish C. Kudva, Aida N. Lteif, Katherine A. Klaus, Surendra Dasari, K. Sreekumaran Nair, Hang Joon Jo, Ronald C. Petersen, Jan Mendelt Tillema

المصدر: JCI Insight, Vol 6, Iss 5 (2021)
JCI Insight

مصطلحات موضوعية: Adult, Blood Glucose, Male, 0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, Pilot Projects, Phosphocreatine, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Memory, Diabetes mellitus, Internal medicine, Fractional anisotropy, medicine, Insulin, Humans, Dementia, Cognitive Dysfunction, Sensory cortex, Translational Science, Biomedical, Type 1 diabetes, business.industry, Diabetes, Cognition, Somatosensory Cortex, General Medicine, medicine.disease, Diabetes Mellitus, Type 1, 030104 developmental biology, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Medicine, Female, Clinical Medicine, business

الوصف: BACKGROUND Type 1 diabetes (T1D) is a risk factor for dementia and structural brain changes. It remains to be determined whether transient insulin deprivation that frequently occurs in insulin-treated individuals with T1D alters brain function. METHODS We therefore performed functional and structural magnetic resonance imaging, magnetic resonance spectroscopy, and neuropsychological testing at baseline and following 5.4 ± 0.6 hours of insulin deprivation in 14 individuals with T1D and compared results with those from 14 age-, sex-, and BMI-matched nondiabetic (ND) participants with no interventions. RESULTS Insulin deprivation in T1D increased blood glucose, and β-hydroxybutyrate, while reducing bicarbonate levels. Participants with T1D showed lower baseline brain N-acetyl aspartate and myo-inositol levels but higher cortical fractional anisotropy, suggesting unhealthy neurons and brain microstructure. Although cognitive functions did not differ between participants with T1D and ND participants at baseline, significant changes in fine motor speed as well as attention and short-term memory occurred following insulin deprivation in participants with T1D. Insulin deprivation also reduced brain adenosine triphosphate levels and altered the phosphocreatine/adenosine triphosphate ratio. Baseline differences in functional connectivity in brain regions between participants with T1D and ND participants were noted, and on insulin deprivation further alterations in functional connectivity between regions, especially cortical and hippocampus-caudate regions, were observed. These alterations in functional connectivity correlated to brain metabolites and to changes in cognition. CONCLUSION Transient insulin deprivation therefore caused alterations in executive aspects of cognitive function concurrent with functional connectivity between memory regions and the sensory cortex. These findings have important clinical implications, as many patients with T1D inadvertently have periods of transient insulin deprivation. TRIAL REGISTRATION ClinicalTrials.gov NCT03392441. FUNDING Clinical and Translational Science Award (UL1 TR002377) from the National Center for Advancing Translational Science; NIH grants (R21 AG60139 and R01 AG62859); the Mayo Foundation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::df35e605fd35bca18e9e9717df343f45Test
https://doaj.org/article/89e91ea96c224a14803019bb961e2cc3Test

المؤلفون: Elisavet Serti, Todd M. Brusko, Keshav Motwani, Fariba Barahmand-pour-Whitman, Karen Cerosaletti, Colin O’Rourke, Alex Hu, Peter S. Linsley, Janice Chen, Gerald T. Nepom, Elisa Balmas, Carla J. Greenbaum, Cate Speake, William W. Kwok, Hannah A. DeBerg, Kaitlin J. Flynn, Mario G. Rosasco, Howard R. Seay, Vivian H. Gersuk

المصدر: JCI Insight

مصطلحات موضوعية: Adult, Male, Adolescent, Population, Receptors, Antigen, T-Cell, chemical and pharmacologic phenomena, Autoimmunity, Biology, medicine.disease_cause, Immunoglobulin alpha-Chains, Germline, Epitope, Young Adult, Antigen, medicine, Humans, CD154, education, education.field_of_study, T-cell receptor, RNA, hemic and immune systems, General Medicine, Cell biology, Diabetes Mellitus, Type 1, Germ Cells, Resource and Technical Advance, Female, T cell receptor

الوصف: Human islet antigen reactive CD4+ memory T cells (IAR T cells) play a key role in the pathogenesis of autoimmune type 1 diabetes (T1D). Using single-cell RNA sequencing (scRNA-Seq) to identify T cell receptors (TCRs) in IAR T cells, we have identified a class of TCRs that share TCRα chains between individuals ("public" chains). We isolated IAR T cells from blood of healthy, new-onset T1D and established T1D donors using multiplexed CD154 enrichment and identified paired TCRαβ sequences from 2767 individual cells. More than a quarter of cells shared TCR junctions between 2 or more cells ("expanded"), and 29/47 (~62%) of expanded TCRs tested showed specificity for islet antigen epitopes. Public TCRs sharing TCRα junctions were most prominent in new-onset T1D. Public TCR sequences were more germline like than expanded unique, or "private," TCRs, and had shorter junction sequences, suggestive of fewer random nucleotide insertions. Public TCRα junctions were often paired with mismatched TCRβ junctions in TCRs; remarkably, a subset of these TCRs exhibited cross-reactivity toward distinct islet antigen peptides. Our findings demonstrate a prevalent population of IAR T cells with diverse specificities determined by TCRs with restricted TCRα junctions and germline-constrained antigen recognition properties. Since these "innate-like" TCRs differ from previously described immunodominant TCRβ chains in autoimmunity, they have implications for fundamental studies of disease mechanisms. Self-reactive restricted TCRα chains and their associated epitopes should be considered in fundamental and translational investigations of TCRs in T1D.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::16ac74b43405ccf18113a29d94d5a638Test
http://europepmc.org/articles/PMC8663791Test

المؤلفون: Mark Harris, Ranjeny Thomas, Martin J. Hessner, Rhonda Geoffrey, Anne-Sophie Bergot, Breanna Lam, Kerry Buchanan, Elisavet Serti, Rosita Moya, Alessandra Mandelli, Irene Gotuzzo, Manuela Battaglia, Joanna D. Davies, Aditi Narsale, Benedetta Pessina, Gian Maria Giamporcaro, TingTing Lu

المصدر: JCI Insight, Vol 6, Iss 2 (2021)
JCI Insight

مصطلحات موضوعية: CD4-Positive T-Lymphocytes, Male, 0301 basic medicine, Oncology, Autoimmune diseases, medicine.medical_treatment, Cell, Autoimmunity, medicine.disease_cause, 0302 clinical medicine, T-Lymphocyte Subsets, IL-2 receptor, Child, education.field_of_study, Diabetes, General Medicine, medicine.anatomical_structure, Child, Preschool, 030220 oncology & carcinogenesis, Disease Progression, Medicine, Female, Immunotherapy, Research Article, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Population, Immunology, T cells, Alefacept, Interleukin-7 Receptor alpha Subunit, Young Adult, 03 medical and health sciences, Diabetes mellitus, Internal medicine, medicine, Humans, education, Proportional Hazards Models, Type 1 diabetes, business.industry, Interleukin-2 Receptor alpha Subunit, Infant, medicine.disease, Diabetes Mellitus, Type 1, 030104 developmental biology, Multivariate Analysis, business

الوصف: Transient partial remission, a period of low insulin requirement experienced by most patients soon after diagnosis, has been associated with mechanisms of immune regulation. A better understanding of such natural mechanisms of immune regulation might identify new targets for immunotherapies that reverse type 1 diabetes (T1D). In this study, using Cox model multivariate analysis, we validated our previous findings that patients with the highest frequency of CD4+CD25+CD127hi (127-hi) cells at diagnosis experience the longest partial remission, and we showed that the 127-hi cell population is a mix of Th1- and Th2-type cells, with a significant bias toward antiinflammatory Th2-type cells. In addition, we extended these findings to show that patients with the highest frequency of 127-hi cells at diagnosis were significantly more likely to maintain β cell function. Moreover, in patients treated with alefacept in the T1DAL clinical trial, the probability of responding favorably to the antiinflammatory drug was significantly higher in those with a higher frequency of 127-hi cells at diagnosis than those with a lower 127-hi cell frequency. These data are consistent with the hypothesis that 127-hi cells maintain an antiinflammatory environment that is permissive for partial remission, β cell survival, and response to antiinflammatory immunotherapy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b18ca9272dda4aa45bece327b8ae55f8Test
https://doaj.org/article/20ba8c4ce6b4454ea7c69dca229e3557Test