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Article ; Online: Human T

2023 Volume 24, Issue 2, Page(s) 295–308

Abstract: ... Whether T cells utilize innate immune signaling pathways to diversify their repertoire of effector functions is ... T cells express GSDME and, surprisingly, that this expression is associated with durable viability and ... of human helper type 17 T cells with specificity for Candida albicans and regulated by a T cell-intrinsic ...

Abstract	It has been shown that innate immune responses can adopt adaptive properties such as memory. Whether T cells utilize innate immune signaling pathways to diversify their repertoire of effector functions is unknown. Gasdermin E (GSDME) is a membrane pore-forming molecule that has been shown to execute pyroptotic cell death and thus to serve as a potential cancer checkpoint. In the present study, we show that human T cells express GSDME and, surprisingly, that this expression is associated with durable viability and repurposed for the release of the alarmin interleukin (IL)-1α. This property was restricted to a subset of human helper type 17 T cells with specificity for Candida albicans and regulated by a T cell-intrinsic NLRP3 inflammasome, and its engagement of a proteolytic cascade of successive caspase-8, caspase-3 and GSDME cleavage after T cell receptor stimulation and calcium-licensed calpain maturation of the pro-IL-1α form. Our results indicate that GSDME pore formation in T cells is a mechanism of unconventional cytokine release. This finding diversifies our understanding of the functional repertoire and mechanistic equipment of T cells and has implications for antifungal immunity.
MeSH term(s)	Humans ; Caspase 1/metabolism ; Gasdermins ; Immunity, Innate ; Inflammasomes/metabolism ; Interleukin-1beta/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Pyroptosis ; Th17 Cells
Chemical Substances	Caspase 1 (EC 3.4.22.36) ; Gasdermins ; Inflammasomes ; Interleukin-1beta ; NLR Family, Pyrin Domain-Containing 3 Protein
Language	English
Publishing date	2023-01-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-022-01386-w
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Article ; Online: PRESUMPTIVE RECURRENCE OF INTRAOCULAR LYMPHOMA DESPITE CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY.

Taher, Amir / Abadir, Edward / McCluskey, Peter / Hamad, Nada / Lo, Tsun-Ho / Heydon, Peter

Retinal cases & brief reports

2023 Volume 17, Issue 5, Page(s) 562–566

Abstract: ... following Chimeric Antigen Receptor (CAR) T-cell therapy despite systemic control by CD19-CAR T ... stem cell transplantation but relapsed again and was scheduled to receive CAR T-cell therapy. He developed vitritis ... several weeks before treatment, with vitreous biopsy showing non-Hodgkin B-cell lymphoma. He received CAR T-cell ...

Abstract	Purpose: To present the first reported case of presumptive intraocular recurrence of lymphoma following Chimeric Antigen Receptor (CAR) T-cell therapy despite systemic control by CD19-CAR T cells. Methods: Observational case report. Results: A 59-year-old man with diffuse, large, B-cell lymphoma subsequently developed secondary central nervous system disease despite chemotherapy. He underwent stem cell transplantation but relapsed again and was scheduled to receive CAR T-cell therapy. He developed vitritis several weeks before treatment, with vitreous biopsy showing non-Hodgkin B-cell lymphoma. He received CAR T-cell therapy following the vitrectomy. He presented 3 months following CAR T-cell therapy with nonspecific right eye floaters and discomfort, with the optical coherence tomography revealing subretinal saw-tooth deposits in the right eye, highly suggestive of lymphoma. This is despite having good systemic control with no other disease elsewhere in the body. He received intravitreal methotrexate to good effect. Conclusion: To our knowledge, this is the first case of a vitreoretinal lymphoma nonresponsive to CAR T-cell therapy, despite good central nervous system and systemic control. This is suggestive of anti-CD19 CAR T cells not trafficking into the eye in sufficient numbers to eliminate CD19-expressing neoplastic B cells. We suggest regular ophthalmic follow-up after CAR-T-cell therapy for patients where there is evidence of ocular involvement.
MeSH term(s)	Male ; Humans ; Middle Aged ; Intraocular Lymphoma/diagnosis ; Intraocular Lymphoma/therapy ; Receptors, Chimeric Antigen/therapeutic use ; Immunotherapy, Adoptive ; Retinal Neoplasms/diagnosis ; Retinal Neoplasms/therapy ; Vitreous Body ; Eye Neoplasms/therapy ; Central Nervous System Neoplasms ; Lymphoma, Large B-Cell, Diffuse ; Adaptor Proteins, Signal Transducing ; Cell- and Tissue-Based Therapy
Chemical Substances	Receptors, Chimeric Antigen ; Adaptor Proteins, Signal Transducing
Language	English
Publishing date	2023-08-29
Publishing country	United States
Document type	Observational Study ; Case Reports ; Journal Article
ISSN	1937-1578
ISSN (online)	1937-1578
DOI	10.1097/ICB.0000000000001246
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Article ; Online: Butyrophilin 2a2 (Btn2a2) expression on thymic epithelial cells promotes central T cell tolerance and prevents autoimmune disease.

Frech, Michael / Danzer, Heike / Uchil, Pooja / Azizov, Vugar / Schmid, Eva / Schälter, Fabian / Dürholz, Kerstin / Mauro, Daniele / Rauber, Simon / Muñoz, Luis / Taher, Leila / Ciccia, Francesco / Schober, Kilian / Irla, Magali / Sarter, Kerstin / Schett, Georg / Zaiss, Mario M

Journal of autoimmunity

2023 Volume 139, Page(s) 103071

Abstract: ... While several members of the butyrophilin family have been implicated in the development of unconventional T ... cells, butyrophilin 2a2 (Btn2a2) has been shown to inhibit conventional T cell activation. Here, we demonstrate ... thymic T cell maturation and bypasses central tolerance mechanisms. Furthermore, Btn2a2 ...

Abstract	Butyrophilins are surface receptors belonging to the immunoglobulin superfamily. While several members of the butyrophilin family have been implicated in the development of unconventional T cells, butyrophilin 2a2 (Btn2a2) has been shown to inhibit conventional T cell activation. Here, we demonstrate that in steady state, the primary source of Btn2a2 are thymic epithelial cells (TEC). Absence of Btn2a2 alters thymic T cell maturation and bypasses central tolerance mechanisms. Furthermore, Btn2a2
MeSH term(s)	Mice ; Humans ; Animals ; Butyrophilins/genetics ; Central Tolerance ; Thymus Gland ; Epithelial Cells ; Autoimmune Diseases ; Receptors, Antigen, T-Cell/genetics
Chemical Substances	Butyrophilins ; Receptors, Antigen, T-Cell ; Btn2a2 protein, mouse
Language	English
Publishing date	2023-06-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639452-8
ISSN	1095-9157 ; 0896-8411
ISSN (online)	1095-9157
ISSN	0896-8411
DOI	10.1016/j.jaut.2023.103071
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Article ; Online: Late gene expression-deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIV.

Hansen, Scott G / Womack, Jennie L / Perez, Wilma / Schmidt, Kimberli A / Marshall, Emily / Iyer, Ravi F / Cleveland Rubeor, Hillary / Otero, Claire E / Taher, Husam / Vande Burgt, Nathan H / Barfield, Richard / Randall, Kurt T / Morrow, David / Hughes, Colette M / Selseth, Andrea N / Gilbride, Roxanne M / Ford, Julia C / Caposio, Patrizia / Tarantal, Alice F /

Chan, Cliburn / Malouli, Daniel / Barry, Peter A / Permar, Sallie R / Picker, Louis J / Früh, Klaus

JCI insight

2023 Volume 8, Issue 6

Abstract: ... biased) CD8+ T cells recognizing SIV peptides presented by major histocompatibility complex-E (MHC-E ... Rh108-deficient 68-1 RhCMV/SIV vectors elicited high-frequency, durable, EM-biased, SIV-specific T cell ... responses in RhCMV-seropositive RMs at doses of ≥ 1 × 106 PFU. Strikingly, elicited CD8+ T cells exclusively ...

Abstract	Rhesus cytomegalovirus-based (RhCMV-based) vaccine vectors induce immune responses that protect ~60% of rhesus macaques (RMs) from SIVmac239 challenge. This efficacy depends on induction of effector memory-based (EM-biased) CD8+ T cells recognizing SIV peptides presented by major histocompatibility complex-E (MHC-E) instead of MHC-Ia. The phenotype, durability, and efficacy of RhCMV/SIV-elicited cellular immune responses were maintained when vector spread was severely reduced by deleting the antihost intrinsic immunity factor phosphoprotein 71 (pp71). Here, we examined the impact of an even more stringent attenuation strategy on vector-induced immune protection against SIV. Fusion of the FK506-binding protein (FKBP) degradation domain to Rh108, the orthologue of the essential human CMV (HCMV) late gene transcription factor UL79, generated RhCMV/SIV vectors that conditionally replicate only when the FK506 analog Shield-1 is present. Despite lacking in vivo dissemination and reduced innate and B cell responses to vaccination, Rh108-deficient 68-1 RhCMV/SIV vectors elicited high-frequency, durable, EM-biased, SIV-specific T cell responses in RhCMV-seropositive RMs at doses of ≥ 1 × 106 PFU. Strikingly, elicited CD8+ T cells exclusively targeted MHC-Ia-restricted epitopes and failed to protect against SIVmac239 challenge. Thus, Rh108-dependent late gene expression is required for both induction of MHC-E-restricted T cells and protection against SIV.
MeSH term(s)	Animals ; Humans ; Cytomegalovirus/genetics ; Simian Immunodeficiency Virus ; Macaca mulatta ; Gene Expression
Language	English
Publishing date	2023-03-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.164692
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Article ; Online: Btn2a2 Regulates ILC2-T Cell Cross Talk in Type 2 Immune Responses.

Frech, Michael / Omata, Yasunori / Schmalzl, Angelika / Wirtz, Stefan / Taher, Leila / Schett, Georg / Zaiss, Mario M / Sarter, Kerstin

Frontiers in immunology

2022 Volume 13, Page(s) 757436

Abstract: ... but also actively modulate T cell responses. However, the molecular processes regulating ILC-T ... molecule first identified on antigen-presenting cells, has a pivotal role in the maintenance of T cell ... of Btn2a2 in the ILC-T cell cross talk. We found that the expression of Btn2a2 is upregulated in ILC2 ...

Abstract	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.
MeSH term(s)	Animals ; Biomarkers ; Butyrophilins/genetics ; Butyrophilins/metabolism ; Cell Communication/immunology ; Epitopes, T-Lymphocyte/immunology ; Helminthiasis/genetics ; Helminthiasis/immunology ; Helminthiasis/parasitology ; Helminths/immunology ; Host-Pathogen Interactions/genetics ; Host-Pathogen Interactions/immunology ; Immunity, Innate ; Immunomodulation ; Immunophenotyping ; Mice ; Mice, Knockout ; Parasite Load ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism
Chemical Substances	Biomarkers ; Btn2a2 protein, mouse ; Butyrophilins ; Epitopes, T-Lymphocyte
Language	English
Publishing date	2022-01-25
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.757436
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Article ; Online: Transcriptional profiling of human Vδ1 T cells reveals a pathogen-driven adaptive differentiation program.

Cell reports

2022 Volume 39, Issue 8, Page(s) 110858

Abstract: γδ T cells are generally considered innate-like lymphocytes, however, an "adaptive-like" γδ ... compartment has now emerged. To understand transcriptional regulation of adaptive γδ T cell immunobiology ... we combined single-cell transcriptomics, T cell receptor (TCR)-clonotype assignment, ATAC-seq, and ...

Abstract	γδ T cells are generally considered innate-like lymphocytes, however, an "adaptive-like" γδ compartment has now emerged. To understand transcriptional regulation of adaptive γδ T cell immunobiology, we combined single-cell transcriptomics, T cell receptor (TCR)-clonotype assignment, ATAC-seq, and immunophenotyping. We show that adult Vδ1
MeSH term(s)	Adult ; CD8-Positive T-Lymphocytes/metabolism ; Cell Differentiation ; Child, Preschool ; Granzymes/metabolism ; Humans ; Receptors, Antigen, T-Cell, gamma-delta/metabolism ; T-Lymphocyte Subsets/metabolism
Chemical Substances	Receptors, Antigen, T-Cell, gamma-delta ; Granzymes (EC 3.4.21.-)
Language	English
Publishing date	2022-05-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2022.110858
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Article ; Online: Bicyclic azetidines target acute and chronic stages of Toxoplasma gondii by inhibiting parasite phenylalanyl t-RNA synthetase.

Radke, Joshua B / Melillo, Bruno / Mittal, Payal / Sharma, Manmohan / Sharma, Amit / Fu, Yong / Uddin, Taher / Gonse, Arthur / Comer, Eamon / Schreiber, Stuart L / Gupta, Anil K / Chatterjee, Arnab K / Sibley, L David

Nature communications

2022 Volume 13, Issue 1, Page(s) 459

Abstract: ... of phenylalanine tRNA synthetase (PheRS) in T. gondii, with excellent selectivity. Biochemical and genetic studies ... validate PheRS as the primary target of bicyclic azetidines in T. gondii, providing a structural basis ...

Abstract	Toxoplasma gondii commonly infects humans and while most infections are controlled by the immune response, currently approved drugs are not capable of clearing chronic infection in humans. Hence, approximately one third of the world's human population is at risk of reactivation, potentially leading to severe sequelae. To identify new candidates for treating chronic infection, we investigated a series of compounds derived from diversity-oriented synthesis. Bicyclic azetidines are potent low nanomolar inhibitors of phenylalanine tRNA synthetase (PheRS) in T. gondii, with excellent selectivity. Biochemical and genetic studies validate PheRS as the primary target of bicyclic azetidines in T. gondii, providing a structural basis for rational design of improved analogs. Favorable pharmacokinetic properties of a lead compound provide excellent protection from acute infection and partial protection from chronic infection in an immunocompromised mouse model of toxoplasmosis. Collectively, PheRS inhibitors of the bicyclic azetidine series offer promise for treatment of chronic toxoplasmosis.
MeSH term(s)	Animals ; Antiprotozoal Agents/administration & dosage ; Antiprotozoal Agents/chemistry ; Azetidines/administration & dosage ; Azetidines/chemistry ; Enzyme Inhibitors/administration & dosage ; Enzyme Inhibitors/chemistry ; Female ; Humans ; Kinetics ; Male ; Mice ; Mice, Inbred CBA ; Phenylalanine-tRNA Ligase/antagonists & inhibitors ; Phenylalanine-tRNA Ligase/chemistry ; Phenylalanine-tRNA Ligase/metabolism ; Protozoan Proteins/antagonists & inhibitors ; Protozoan Proteins/chemistry ; Protozoan Proteins/metabolism ; Toxoplasma/drug effects ; Toxoplasma/enzymology ; Toxoplasma/genetics ; Toxoplasma/growth & development ; Toxoplasmosis/drug therapy ; Toxoplasmosis/parasitology
Chemical Substances	Antiprotozoal Agents ; Azetidines ; Enzyme Inhibitors ; Protozoan Proteins ; azetidine (37S883XDWR) ; Phenylalanine-tRNA Ligase (EC 6.1.1.20)
Language	English
Publishing date	2022-01-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-28108-y
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Article ; Online: Cytomegalovirus-vaccine-induced unconventional T cell priming and control of SIV replication is conserved between primate species.

Malouli, Daniel / Gilbride, Roxanne M / Wu, Helen L / Hwang, Joseph M / Maier, Nicholas / Hughes, Colette M / Newhouse, Daniel / Morrow, David / Ventura, Abigail B / Law, Lynn / Tisoncik-Go, Jennifer / Whitmore, Leanne / Smith, Elise / Golez, Inah / Chang, Jean / Reed, Jason S / Waytashek, Courtney / Weber, Whitney / Taher, Husam /

Uebelhoer, Luke S / Womack, Jennie L / McArdle, Matthew R / Gao, Junwei / Papen, Courtney R / Lifson, Jeffrey D / Burwitz, Benjamin J / Axthelm, Michael K / Smedley, Jeremy / Früh, Klaus / Gale, Michael / Picker, Louis J / Hansen, Scott G / Sacha, Jonah B

Cell host & microbe

2022 Volume 30, Issue 9, Page(s) 1207–1218.e7

Abstract: ... SIV) primes MHC-E-restricted CD8+ T cells that control SIV replication in 50%-60% of the vaccinated ... T cells requires matching CMV to its host species. RhCMV does not elicit MHC-E-restricted CD8+ T ... CyCMV/SIV mounted MHC-E-restricted CD8+ T cells, and half of the vaccinees stringently controlled SIV ...

Abstract	Strain 68-1 rhesus cytomegalovirus expressing simian immunodeficiency virus (SIV) antigens (RhCMV/SIV) primes MHC-E-restricted CD8+ T cells that control SIV replication in 50%-60% of the vaccinated rhesus macaques. Whether this unconventional SIV-specific immunity and protection is unique to rhesus macaques or RhCMV or is intrinsic to CMV remains unknown. Here, using cynomolgus CMV vectors expressing SIV antigens (CyCMV/SIV) and Mauritian cynomolgus macaques, we demonstrate that the induction of MHC-E-restricted CD8+ T cells requires matching CMV to its host species. RhCMV does not elicit MHC-E-restricted CD8+ T cells in cynomolgus macaques. However, cynomolgus macaques vaccinated with species-matched 68-1-like CyCMV/SIV mounted MHC-E-restricted CD8+ T cells, and half of the vaccinees stringently controlled SIV post-challenge. Protected animals manifested a vaccine-induced IL-15 transcriptomic signature that is associated with efficacy in rhesus macaques. These findings demonstrate that the ability of species-matched CMV vectors to elicit MHC-E-restricted CD8+ T cells that are required for anti-SIV efficacy is conserved in nonhuman primates, and these data support the development of HCMV/HIV for a prophylactic HIV vaccine.
MeSH term(s)	AIDS Vaccines ; Animals ; CD8-Positive T-Lymphocytes ; Cytomegalovirus/genetics ; Cytomegalovirus Infections ; Cytomegalovirus Vaccines ; Interleukin-15 ; Macaca fascicularis ; Macaca mulatta ; SAIDS Vaccines ; Simian Acquired Immunodeficiency Syndrome ; Simian Immunodeficiency Virus
Chemical Substances	AIDS Vaccines ; Cytomegalovirus Vaccines ; Interleukin-15 ; SAIDS Vaccines
Language	English
Publishing date	2022-08-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2278004-X
ISSN	1934-6069 ; 1931-3128
ISSN (online)	1934-6069
ISSN	1931-3128
DOI	10.1016/j.chom.2022.07.013
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Zs.A 6578: Show issues

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Book ; Online: Fast Facts

Taher, Ali T.

Thalassemia Syndromes

(Fast facts)

2023

Abstract: Fast Facts: Thalassemia Syndromes' provides a concise, comprehensive introduction to the thalassemia syndromes and current approaches to treating them and their associated morbidities. ...

Author's details	Ali T. Taher [and three others]
Series title	Fast facts
Abstract	'Fast Facts: Thalassemia Syndromes' provides a concise, comprehensive introduction to the thalassemia syndromes and current approaches to treating them and their associated morbidities.
Keywords	Hematology ; Blood/Diseases
Subject code	616.15
Language	English
Size	1 online resource (72 pages).
Publisher	Karger AG
Publishing place	Oxford, England
Document type	Book ; Online
ISBN	3-318-07206-0 ; 9783318071498 ; 978-3-318-07206-8 ; 3318071498
Database	ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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Article ; Online: Altered distributions and functions of natural killer T cells and γδ T cells in neonates with neonatal encephalopathy, in school-age children at follow-up, and in children with cerebral palsy.

Taher, Nawal A B / Kelly, Lynne A / Al-Harbi, Alhanouf I / O'Dea, Mary I / Zareen, Zunera / Ryan, Emer / Molloy, Eleanor J / Doherty, Derek G

Journal of neuroimmunology

2021 Volume 356, Page(s) 577597

Abstract: ... flow cytometry, we demonstrate alterations in circulating T, B and natural killer cell numbers. Invariant natural ... killer T cell and Vδ2 ...

Abstract	We enumerated conventional and innate lymphocyte populations in neonates with neonatal encephalopathy (NE), school-age children post-NE, children with cerebral palsy and age-matched controls. Using flow cytometry, we demonstrate alterations in circulating T, B and natural killer cell numbers. Invariant natural killer T cell and Vδ2
MeSH term(s)	Brain Diseases/blood ; Brain Diseases/diagnosis ; Brain Diseases/immunology ; Cerebral Palsy/blood ; Cerebral Palsy/diagnosis ; Cerebral Palsy/immunology ; Child ; Female ; Follow-Up Studies ; Humans ; Infant, Newborn ; Male ; Natural Killer T-Cells/immunology ; Natural Killer T-Cells/metabolism ; Receptors, Antigen, T-Cell, gamma-delta/blood ; Receptors, Antigen, T-Cell, gamma-delta/immunology ; Students ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism
Chemical Substances	Receptors, Antigen, T-Cell, gamma-delta
Language	English
Publishing date	2021-04-29
Publishing country	Netherlands
Document type	Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	8335-5
ISSN	1872-8421 ; 0165-5728
ISSN (online)	1872-8421
ISSN	0165-5728
DOI	10.1016/j.jneuroim.2021.577597
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