scholarly journals The Bloom's Syndrome Helicase Is Critical for Development and Function of the αβ T-Cell Lineage

2007 ◽  
Vol 27 (5) ◽  
pp. 1947-1959 ◽  
Author(s):  
Holger Babbe ◽  
Nicholas Chester ◽  
Philip Leder ◽  
Boris Reizis
Keyword(s):  
T Cell ◽  
Genetic Disorder ◽  
Cell Lineage ◽  
Unknown Origin ◽  
Cell Receptor ◽  
Dna Helicase ◽  
Vital Role ◽  
Bloom's Syndrome ◽  
Bloom’S Syndrome ◽  
And Function

ABSTRACT Bloom's syndrome is a genetic disorder characterized by increased incidence of cancer and an immunodeficiency of unknown origin. The BLM gene mutated in Bloom's syndrome encodes a DNA helicase involved in the maintenance of genomic integrity. To explore the role of BLM in the immune system, we ablated murine Blm in the T-cell lineage. In the absence of Blm, thymocytes were severely reduced in numbers and displayed a developmental block at the β-selection checkpoint that was partially p53 dependent. Blm-deficient thymocytes rearranged their T-cell receptor (TCR) β genes normally yet failed to survive and proliferate in response to pre-TCR signaling. Furthermore, peripheral T cells were reduced in numbers, manifested defective homeostatic and TCR-induced proliferation, and produced extensive chromosomal damage. Finally, CD4+ and CD8+ T-cell responses were impaired upon antigen challenge. Thus, by ensuring genomic stability, Blm serves a vital role for development, maintenance, and function of T lymphocytes, suggesting a basis for the immune deficiency in Bloom's syndrome.

scholarly journals Mutation of the Murine Bloom's Syndrome Gene Produces Global Genome Destabilization

2006 ◽  
Vol 26 (17) ◽  
pp. 6713-6726 ◽  
Author(s):  
Nicholas Chester ◽  
Holger Babbe ◽  
Jan Pinkas ◽  
Charlene Manning ◽  
Philip Leder
Keyword(s):  
Cell Lines ◽  
Human Cancer ◽  
Genetic Disorder ◽  
Dna Helicase ◽  
Sister Chromatid Exchanges ◽  
Conditional Knockout ◽  
Chromosome Loss ◽  
Bloom's Syndrome ◽  
Bloom’S Syndrome

ABSTRACT Bloom's syndrome (BS) is a genetic disorder characterized cellularly by increases in sister chromatid exchanges (SCEs) and numbers of micronuclei. BS is caused by mutation in the BLM DNA helicase gene and involves a greatly enhanced risk of developing the range of malignancies seen in the general population. With a mouse model for the disease, we set out to determine the relationship between genomic instability and neoplasia. We used a novel two-step analysis to investigate a panel of eight cell lines developed from mammary tumors that appeared in Blm conditional knockout mice. First, the panel of cell lines was examined for instability. High numbers of SCEs were uniformly seen in members of the panel, and several lines produced chromosomal instability (CIN) manifested by high numbers of chromosomal structural aberrations (CAs) and chromosome missegregation events. Second, to see if Blm mutation was responsible for the CIN, time-dependent analysis was conducted on a tumor line harboring a functional floxed Blm allele. The floxed allele was deleted in vitro, and mutant as well as control subclones were cultured for 100 passages. By passage 100, six of nine mutant subclones had acquired high CIN. Nine mutant subclones produced 50-fold more CAs than did nine control subclones. Finally, chromosome loss preceded the appearance of CIN, suggesting that this loss provides a potential mechanism for the induction of instability in mutant subclones. Such aneuploidy or CIN is a universal feature of neoplasia but has an uncertain function in oncogenesis. Our results show that Blm gene mutation produces this instability, strengthening a role for CIN in the development of human cancer.

scholarly journals Commitment of Common T/Natural Killer (Nk) Progenitors to Unipotent T and Nk Progenitors in the Murine Fetal Thymus Revealed by a Single Progenitor Assay

1999 ◽  
Vol 190 (11) ◽  
pp. 1617-1626 ◽  
Author(s):  
Tomokatsu Ikawa ◽  
Hiroshi Kawamoto ◽  
Shinji Fujimoto ◽  
Yoshimoto Katsura
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
T Cell Receptor ◽  
Cell Lineage ◽  
Cell Receptor ◽  
The Other ◽  
Fetal Thymus ◽  
Β Chain ◽  
Clonal Assay

We have established a new clonal assay system that can evenly support the development of T and natural killer (NK) cells. With this system, we show that all T cell progenitors in the earliest CD44+CD25−FcγRII/III− fetal thymus (FT) cell population retain NK potential, and that the NK lineage–committed progenitors (p-NK) also exist in this population. T cell lineage–committed progenitors (p-T), which are unable to generate NK cells, first appear at the CD44+CD25− FcγRII/III+ stage in day 12 FT. The proportion of p-T markedly increases during the transition from the CD44+CD25− stage to the CD44+CD25+ stage in day 14 FT. On the other hand, p-NK preferentially increase in number at the CD44+CD25− stage between days 12 and 14 of gestation. The production of p-NK continues up to the CD44+CD25+ stage, but ceases before the rearrangement of T cell receptor β chain genes. It was further shown that the CD44+CD25− CD122+ population of day 14 FT exclusively contains p-NK. These results indicate that the earliest T cell progenitor migrating into the FT is T/NK bipotent, and strongly suggest that the bipotent progenitor continuously produces p-NK and p-T until the CD44+CD25+ stage.

scholarly journals 173 Expression of a membrane-tethered IL-15/IL-15 receptor fusion protein enhances the persistence of MSLN-targeted TRuC-T cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A185-A185
Author(s):  
Michelle Fleury ◽  
Derrick McCarthy ◽  
Holly Horton ◽  
Courtney Anderson ◽  
Amy Watt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Fusion Protein ◽  
T Cell Receptor ◽  
Cytokine Production ◽  
Cell Receptor ◽  
Great Promise ◽  
And Function

BackgroundAdoptive cell therapies have shown great promise in hematological malignancies but have yielded little progress in the context of solid tumors. We have developed T cell receptor fusion construct (TRuC®) T cells, which are equipped with an engineered T cell receptor that utilizes the full complement of TCR signaling subunits and recognizes tumor-associated antigens independent of HLA. In clinical trials, mesothelin (MSLN)-targeting TRuC-T cells (TC-210 or gavo-cel) have shown unprecedented results in patients suffering from advanced mesothelioma and ovarian cancer. To potentially increase the depth of response, we evaluated strategies that can promote intra-tumoral T cell persistence and function. Among the common ??-chain cytokines, IL-15 uniquely supports the differentiation and maintenance of memory T cell subsets by limiting terminal differentiation and conferring resistance to IL-2 mediated activation-induced cell death (AICD). In the studies described here, we evaluated the potential of IL-15 as an enhancement to TRuC-T cell phenotype, persistence and function against MSLN+ targets.MethodsPrimary human T cells were activated and transduced with a lentiviral vector encoding an anti-MSLN binder fused to CD3ε alone or co-expressed with a membrane-tethered IL-15rα/IL-15 fusion protein (IL-15fu). Transduced T cells were expanded for 9 days and characterized for expression of the TRuC, IL-15rα and memory phenotype before subjecting them to in vitro functional assays to evaluate cytotoxicity, cytokine production, and persistence. In vivo efficacy was evaluated in MHC class I/II deficient NSG mice bearing human mesothelioma xenografts.ResultsIn vitro, co-expression of the IL-15fu led to similar cytotoxicity and cytokine production as TC-210, but notably enhanced T-cell expansion and persistence upon repeated stimulation with MSLN+ cell lines. Furthermore, the IL-15fu-enhanced TRuC-T cells sustained a significantly higher TCF-1+ population and retained a stem-like phenotype following activation. Moreover, the IL-15fu-enhanced TRuCs demonstrated robust in vivo expansion and intra-tumoral accumulation as measured by ex vivo analysis of TRuC+ cells in the tumor and blood, with a preferential expansion of CD8+ T cells. Finally, IL-15fu-enhanced TRuC-T cells could be observed in the blood long after the tumors were cleared.ConclusionsThese pre-clinical studies suggest that the IL-15fu can synergize with TC-210 to increase the potency and durability of response in patients with MSLN+ tumors.Ethics ApprovalAll animal studies were approved by the respective Institutional Animal Care and Use Committees.

scholarly journals Enhancing and inhibitory motifs have coevolved to regulate CD4 activity

2021 ◽  
Author(s):  
Mark S. Lee ◽  
Peter J. Tuohy ◽  
Caleb Kim ◽  
Katrina Lichauco ◽  
Heather L. Parrish ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Purifying Selection ◽  
Cell Receptor ◽  
Specific Information ◽  
Transmembrane Receptors ◽  
Peptide Antigens ◽  
And Function ◽  
Intracellular Domains

SUMMARYCD4+ T cells use T cell receptor (TCR)-CD3 complexes, and CD4, to respond to peptide antigens within MHCII molecules (pMHCII). We report here that, through ∼435 million years of evolution in jawed vertebrates, purifying selection has shaped motifs in the extracellular, transmembrane, and intracellular domains of eutherian CD4 that both enhance pMHCII responses and are coevolving with residues in an intracellular motif that inhibits pMHCII responses. Importantly, while CD4 interactions with the Src kinase, Lck, are classically viewed as the key determinant of CD4’s contribution to pMHCII responses, we found that without the inhibitory motif CD4-Lck interactions are not necessary for robust responses to pMHCII. In summary, motifs that mediate events on the outside and inside of CD4+ T cells coevolved to finetune the relay of pMHCII-specific information across the membrane. These results have implications for the evolution and function of complex transmembrane receptors and for biomimetic engineering.

scholarly journals Activation via the CD3 and CD16 pathway mediates interleukin-2- dependent autocrine proliferation of granular lymphocytes in patients with granular lymphocyte proliferative disorders

Blood ◽  
1991 ◽  
Vol 78 (12) ◽  
pp. 3232-3240 ◽  
Author(s):  
S Hoshino ◽  
K Oshimi ◽  
M Teramura ◽  
H Mizoguchi
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Nk Cell ◽  
Interleukin 2 ◽  
Cell Lineage ◽  
Cell Receptor ◽  
Cell Phenotype ◽  
Beta Chain ◽  
Alpha Beta ◽  
Granular Lymphocytes

Abstract Granular lymphocytes (GLs) in patients with GL-proliferative disorders (GLPDs) are known to express the interleukin-2 receptor (IL-2R) beta chain (p70–75) constitutively and to proliferate in response to stimulation with IL-2 via the beta chain. In this report, we found that the anti-CD3 monoclonal antibody (MoAb) OKT3 could induce the proliferation of GLs from patients with T-cell lineage GLPDs (T-cell receptor-alpha beta+/CD3+16+), but not that of natural killer (NK) cell lineage GLs (T-cell receptor-alpha beta-/CD3–16+). In contrast, the anti-CD16 MoAb 3G8 that reacts with NK-lineage GLs could induce the proliferation of these GLs but not that of GLs with a T-cell phenotype. Furthermore, the anti-CD16 MoAbs CLB FcR gran1 (VD2) and OK-NK, which react with both T- and NK-lineage GLs, induced the proliferation of GLs with both T- and and NK-cell phenotypes. The proliferative response induced via the CD3 or IgG Fc receptor III (Fc gamma RIII: CD16) pathway was shown to be associated with the IL-2-dependent autocrine pathway by various findings, including the induction of endogenous IL-2 production, the coexpression of the IL-2R alpha chain (p55) and the IL- 2R beta chain, and the inhibition of GL proliferation by anti-IL-2 or anti-IL-2R MoAb. These results suggest that GL proliferation is mediated at least partly through the IL-2-dependent autocrine pathway, and that the TCR/CD3 complex in T-cell phenotype GLs and the Fc gamma RIII in both T- and NK-cell phenotype GLs play a role in their activation in GLPDs.

scholarly journals Irradiation-Mediated Rescue of T Cell–Specific V(D)j Recombination and Thymocyte Differentiation in Severe Combined Immunodeficient Mice by Bone Marrow Cells

1999 ◽  
Vol 190 (9) ◽  
pp. 1257-1262 ◽  
Author(s):  
Chiyu Wang ◽  
Molly A. Bogue ◽  
Jonathan M. Levitt ◽  
David B. Roth
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
T Cell Receptor ◽  
T Lymphocyte ◽  
Bone Marrow Cells ◽  
Cell Lineage ◽  
Cell Receptor ◽  
Immunodeficient Mice ◽  
Thymocyte Differentiation ◽  
Marrow Cells

In SCID (severe combined immunodeficient) mice, proper assembly of immunoglobulin and T cell receptor (TCR) genes is blocked by defective V(D)J recombination so that B and T lymphocyte differentiation is arrested at an early precursor stage. Treating the mice with gamma irradiation rescues V(D)J rearrangement at multiple TCR loci, promotes limited thymocyte differentiation, and induces thymic lymphomas. These effects are not observed in the B cell lineage. Current models postulate that irradiation affects intrathymic T cell precursors. Surprisingly, we found that transfer of irradiated SCID bone marrow cells to unirradiated host animals rescues both TCR rearrangements and thymocyte differentiation. These data indicate that irradiation affects precursor cells at an earlier stage of differentiation than was previously thought and suggest new models for the mechanism of irradiation rescue.

scholarly journals High prevalence of T-cell receptor V delta 2-(D)-D delta 3 or D delta 1/2-D delta 3 rearrangements in B-precursor acute lymphoblastic leukemias

Blood ◽  
1990 ◽  
Vol 75 (9) ◽  
pp. 1834-1840 ◽  
Author(s):  
A Biondi ◽  
P Francia di Celle ◽  
V Rossi ◽  
G Casorati ◽  
G Matullo ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Lymphoblastic Leukemia ◽  
Cell Lineage ◽  
Cell Receptor ◽  
Lymphoproliferative Disorders ◽  
Cell Precursor ◽  
Gene Assembly ◽  
Lymphoid Malignancies ◽  
High Prevalence

Abstract Rearrangement of the immunoglobulin (Ig) and T-cell receptor (TcR) genes generally has been considered a useful marker of B- and T-cell lineage in lymphoproliferative disorders. However, concomitant rearrangements of Ig and TcR genes have been commonly reported in the most immature lymphoid malignancies, mainly in B-cell precursor acute lymphoblastic leukemia (ALL). To better characterize the nature of this lineage promiscuity, we have analyzed the configuration of the TcR delta locus in 75 B-precursor ALL. The large majority of cases (87%) displayed a rearrangement or deletion at the delta locus. Among the 57 nondeletional rearrangements, two patterns were predominant and both appeared to derive from partial joining: a V delta-(D)-D delta 3 (32/57) and a D delta 1/2-D delta 3 (11/57) type. A single V delta gene (V delta 2) appeared to be involved in the first type of rearrangement. These findings are at variance with T-ALL, where rearrangements 5′ to V delta 2 are usually found. It remains to be elucidated whether this incomplete attempt of V delta 2 gene assembly is related to the neoplastic event or represents a physiologic predisposition occurring during early stages of the normal lymphocyte differentiation.

scholarly journals Structure and function of a potent agonist for the semi-invariant natural killer T cell receptor

2005 ◽  
Vol 6 (8) ◽  
pp. 810-818 ◽  
Author(s):  
Dirk M Zajonc ◽  
Carlos Cantu ◽  
Jochen Mattner ◽  
Dapeng Zhou ◽  
Paul B Savage ◽  
...  
Keyword(s):  
T Cell ◽  
Natural Killer ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Structure And Function ◽  
Natural Killer T Cell ◽  
Potent Agonist ◽  
And Function ◽  
Invariant Natural Killer ◽  
Killer T Cell

scholarly journals SOX4 controls invariant NKT cell differentiation by tuning TCR signaling

2018 ◽  
Vol 215 (11) ◽  
pp. 2887-2900 ◽  
Author(s):  
Nidhi Malhotra ◽  
Yilin Qi ◽  
Nicholas A. Spidale ◽  
Michela Frascoli ◽  
Bing Miu ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lineage ◽  
High Mobility ◽  
Allergic Diseases ◽  
Cell Receptor ◽  
Inkt Cells ◽  
Tcr Signaling ◽  
Nkt Cell ◽  
Essential Function ◽  
Lineage Diversification

Natural killer T (NKT) cells expressing the invariant T cell receptor (iTCR) serve an essential function in clearance of certain pathogens and have been implicated in autoimmune and allergic diseases. Complex effector programs of these iNKT cells are wired in the thymus, and upon thymic egress, they can respond within hours of antigenic challenges, classifying iNKT cells as innate-like. It has been assumed that the successful rearrangement of the invariant iTCRα chain is the central event in the divergence of immature thymocytes to the NKT cell lineage, but molecular properties that render the iTCR signaling distinct to permit the T cell lineage diversification remain obscure. Here we show that the High Mobility Group (HMG) transcription factor (TF) SOX4 controls the production of iNKT cells by inducing MicroRNA-181 (Mir181) to enhance TCR signaling and Ca2+ fluxes in precursors. These results suggest the existence of tailored, permissive gene circuits in iNKT precursors for innate-like T cell development.

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