scholarly journals The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+T cells

2020 ◽  
Vol 117 (34) ◽  
pp. 20706-20716 ◽  
Author(s):  
Eliza Mari Kwesi-Maliepaard ◽  
Muhammad Assad Aslam ◽  
Mir Farshid Alemdehy ◽  
Teun van den Brand ◽  
Chelsea McLean ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cell Receptor ◽  
Histone Methyltransferase ◽  
T Cell Differentiation ◽  
Cytotoxic T Cell ◽  
Developmentally Regulated ◽  
Nucleosome Core ◽  
Normal Differentiation

Cytotoxic T cell differentiation is guided by epigenome adaptations, but how epigenetic mechanisms control lymphocyte development has not been well defined. Here we show that the histone methyltransferase DOT1L, which marks the nucleosome core on active genes, safeguards normal differentiation of CD8+T cells. T cell-specific ablation ofDot1Lresulted in loss of naïve CD8+T cells and premature differentiation toward a memory-like state, independent of antigen exposure and in a cell-intrinsic manner. Mechanistically, DOT1L controlled CD8+T cell differentiation by ensuring normal T cell receptor density and signaling. DOT1L also maintained epigenetic identity, in part by indirectly supporting the repression of developmentally regulated genes. Finally, deletion ofDot1Lin T cells resulted in an impaired immune response. Through our study, DOT1L is emerging as a central player in physiology of CD8+T cells, acting as a barrier to prevent premature differentiation and controlling epigenetic integrity.

scholarly journals The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+ T cells

2019 ◽  
Author(s):  
Eliza Mari Kwesi-Maliepaard ◽  
Muhammad Assad Aslam ◽  
Mir Farshid Alemdehy ◽  
Teun van den Brand ◽  
Chelsea McLean ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cytotoxic T Cells ◽  
Cell Receptor ◽  
Histone Methyltransferase ◽  
T Cell Differentiation ◽  
Cytotoxic T Cell

AbstractCytotoxic T-cell differentiation is guided by epigenome adaptations but how epigenetic mechanisms control lymphocyte development has not been well defined. Here we show that the histone methyltransferase DOT1L, which marks the nucleosome core on active genes, safeguards normal differentiation of CD8+ T cells. T-cell specific ablation of Dot1L resulted in loss of naïve CD8+ T cells and premature differentiation towards a memory-like state, independent of antigen exposure and in a cell-intrinsic manner. Without DOT1L, the memory-like CD8+ cells fail to acquire full effector functions in vitro and in vivo. Mechanistically, DOT1L controlled T-cell differentiation and function by ensuring normal T-cell receptor density and signaling, and by maintaining epigenetic identity, in part by indirectly supporting the repression of developmentally-regulated genes. Through our study DOT1L is emerging as a central player in physiology of CD8+ T cells, acting as a barrier to prevent premature differentiation and supporting the licensing of the full effector potential of cytotoxic T cells.

scholarly journals Continuous activity of Foxo1 is required to prevent anergy and maintain the memory state of CD8+ T cells

2017 ◽  
Vol 215 (2) ◽  
pp. 575-594 ◽  
Author(s):  
Arnaud Delpoux ◽  
Rodrigo Hess Michelini ◽  
Shilpi Verma ◽  
Chen-Yen Lai ◽  
Kyla D. Omilusik ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cd8 T Cells ◽  
Initial Conditions ◽  
T Cell Differentiation ◽  
Cytotoxic T Cell ◽  
Memory State ◽  
Self Renewal ◽  
Cytotoxic T Cell Responses

Upon infection with an intracellular pathogen, cytotoxic CD8+ T cells develop diverse differentiation states characterized by function, localization, longevity, and the capacity for self-renewal. The program of differentiation is determined, in part, by FOXO1, a transcription factor known to integrate extrinsic input in order to specify survival, DNA repair, self-renewal, and proliferation. At issue is whether the state of T cell differentiation is specified by initial conditions of activation or is actively maintained. To study the spectrum of T cell differentiation, we have analyzed an infection with mouse cytomegalovirus, a persistent-latent virus that elicits different cytotoxic T cell responses characterized as acute resolving or inflationary. Our results show that FOXO1 is continuously required for all the phenotypic characteristics of memory-effector T cells such that with acute inactivation of the gene encoding FOXO1, T cells revert to a short-lived effector phenotype, exhibit reduced viability, and manifest characteristics of anergy.

scholarly journals A clinically applicable and scalable method to regenerate T-cells from iPSCs for off-the-shelf T-cell immunotherapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shoichi Iriguchi ◽  
Yutaka Yasui ◽  
Yohei Kawai ◽  
Suguru Arima ◽  
Mihoko Kunitomo ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
T Cell Differentiation ◽  
Cytotoxic T Cell ◽  
Cell Immunotherapy ◽  
T Cell Clone ◽  
Cell Commitment ◽  
Differentiation Efficiency ◽  
T Cell Immunotherapy

AbstractClinical successes demonstrated by chimeric antigen receptor T-cell immunotherapy have facilitated further development of T-cell immunotherapy against wide variety of diseases. One approach is the development of “off-the-shelf” T-cell sources. Technologies to generate T-cells from pluripotent stem cells (PSCs) may offer platforms to produce “off-the-shelf” and synthetic allogeneic T-cells. However, low differentiation efficiency and poor scalability of current methods may compromise their utilities. Here we show improved differentiation efficiency of T-cells from induced PSCs (iPSCs) derived from an antigen-specific cytotoxic T-cell clone, or from T-cell receptor (TCR)-transduced iPSCs, as starting materials. We additionally describe feeder-free differentiation culture systems that span from iPSC maintenance to T-cell proliferation phases, enabling large-scale regenerated T-cell production. Moreover, simultaneous addition of SDF1α and a p38 inhibitor during T-cell differentiation enhances T-cell commitment. The regenerated T-cells show TCR-dependent functions in vitro and are capable of in vivo anti-tumor activity. This system provides a platform to generate a large number of regenerated T-cells for clinical application and investigate human T-cell differentiation and biology.

scholarly journals Analysis of T-cell differentiation antigens in acute lymphatic leukemia using monoclonal antibodies

Blood ◽  
1982 ◽  
Vol 60 (3) ◽  
pp. 752-757
Author(s):  
B Koziner ◽  
D Gebhard ◽  
T Denny ◽  
S McKenzie ◽  
BD Clarkson ◽  
...  
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
Cell Differentiation ◽  
T Cell ◽  
Cytotoxic T Cells ◽  
T Cell Differentiation ◽  
Leukemic Cells ◽  
Phenotypic Analysis ◽  
Lymphatic Leukemia ◽  
Normal Differentiation

Leukemic cells in 134 patients with ALL were analyzed by a panel of mouse monoclonal antibodies. Two antibodies are reactive with all peripheral blood T cells but define different surface antigens (Leu-1 and Leu-4). Two other antibodies react with antigens that are restricted to suppressor/cytotoxic T cells (Leu-2) and to helper T cells (Leu-3). We also used antibodies to the receptor for sheep red blood cells (SRBC) (Leu-5) and to a human “TL-like” antigen that is found on most thymocytes but not in peripheral T cells (Leu-6). An antibody to the human p29.34 “Ia-like” molecule was also tested. Of the 134 ALL patients, 17 had a predominance of SRBC-rosetting (Leu-5+) lymphoblasts (“T” ALL), expressing different surface phenotypes defined by this panel of monoclonal antibodies. These phenotypes were not readily classifiable according to a scheme of sequential stages of normal differentiation proposed. Moreover, the lymphoblasts in 8 of 113 patients not expressing conventional B- to T-cell markers (“null” ALL) reacted with the monoclonal anti-T-cell antibodies. This study suggests that the classification of lymphoblasts in ALL based on the reactivities observed with this panel of mouse monoclonal antibodies is not easily reconciled with current models of normal T-cell differentiation. However, it should be emphasized that the precise sequence of antigenic expression by cells undergoing thymic differentiation is still not fully known, and further phenotypic analysis of ALL cells might contribute to an improved understanding of this malignancy.

scholarly journals Antagonist Peptide Selects Thymocytes Expressing a Class II Major Histocompatibility Complex–restricted T Cell Receptor into the CD8 Lineage

1998 ◽  
Vol 188 (6) ◽  
pp. 1083-1089 ◽  
Author(s):  
Ariane Volkmann ◽  
Thomas Barthlott ◽  
Siegfried Weiss ◽  
Ronald Frank ◽  
Brigitta Stockinger
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Cell Differentiation ◽  
T Cell ◽  
T Cell Receptor ◽  
Mhc Class Ii ◽  
Cell Receptor ◽  
Class Ii ◽  
T Cell Differentiation ◽  
Histocompatibility Complex

CD4/CD8 lineage decision is an important event during T cell maturation in the thymus. CD8 T cell differentiation usually requires corecognition of major histocompatibility complex (MHC) class I by the T cell receptor (TCR) and CD8, whereas CD4 T cells differentiate as a consequence of MHC class II recognition by the TCR and CD4. The involvement of specific peptides in the selection of T cells expressing a particular TCR could be demonstrated so far for the CD8 lineage only. We used mice transgenic for an MHC class II-restricted TCR to investigate the role of antagonistic peptides in CD4 T cell differentiation. Interestingly, antagonists blocked the development of CD4+ cells that normally differentiate in thymus organ culture from those mice, and they induced the generation of CD8+ cells in thymus organ culture from mice impaired in CD4+ cell development (invariant chain–deficient mice). These results are in line with recent observations that antagonistic signals direct differentiation into the CD8 lineage, regardless of MHC specificity.

scholarly journals The thymus and central tolerance

2001 ◽  
Vol 356 (1409) ◽  
pp. 609-616 ◽  
Author(s):  
Jonathan Sprent ◽  
Hidehiro Kishimoto
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Tolerance Induction ◽  
Cell Receptor ◽  
Immunological Tolerance ◽  
T Cell Differentiation ◽  
Central Tolerance ◽  
Mhc Molecules ◽  
Self Antigens

T–cell differentiation in the thymus generates a peripheral repertoire of mature T cells that mounts strong responses to foreign antigens but is largely unresponsive to self–antigens. This state of specific immunological tolerance to self–components involves both central and peripheral mechanisms. Here we review the process whereby many T cells with potential reactivity for self–antigens are eliminated in the thymus during early T–cell differentiation. This process of central tolerance (negative selection) reflects apoptosis and is a consequence of immature T cells receiving strong intracellular signalling through T–cell receptor (TCR) recognition of peptides bound to major histocompatibility complex (MHC) molecules. Central tolerance occurs mainly in the medullary region of the thymus and depends upon contact with peptide–MHC complexes expressed on bone–marrow–derived antigen–presenting cells (APCs); whether tolerance also occurs in the cortex is still controversial. Tolerance induction requires a combination of TCR ligation and co–stimulatory signals. Co–stimulation reflects interaction between complementary molecules on T cells and APCs and probably involves multiple molecules acting in consort, which may account for why deletion of individual molecules with known or potential co–stimulatory function has little or no effect on central tolerance. The range of self–antigens that induce central tolerance is considerable and, via low–level expression in the thymus, may also include tissue–specific antigens; central tolerance to these latter antigens, however, is likely to be limited to high–affinity T cells, leaving low–affinity cells to escape. Tolerance to alloantigens and the possibility of using central tolerance to promote acceptance of allografts are discussed.

scholarly journals Analysis of Thymocyte Development Reveals That the Gtpase Rhoa Is a Positive Regulator of T Cell Receptor Responses in Vivo

2001 ◽  
Vol 194 (7) ◽  
pp. 903-914 ◽  
Author(s):  
Isabelle Corre ◽  
Manuel Gomez ◽  
Susina Vielkind ◽  
Doreen A. Cantrell
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
T Cell Differentiation ◽  
Thymocyte Development

Loss of function of the guanine nucleotide binding protein RhoA blocks pre-T cell differentiation and survival indicating that this GTPase is a critical signaling molecule during early thymocyte development. Previous work has shown that the Rho family GTPase Rac-1 can initiate changes in actin dynamics necessary and sufficient for pre-T cell development. The present data now show that Rac-1 actions in pre-T cells require Rho function but that RhoA cannot substitute for Rac-1 and induce the actin cytoskeletal changes necessary for pre-T cell development. Activation of Rho is thus not sufficient to induce pre-T cell differentiation or survival in the absence of the pre-T cell receptor (TCR). The failure of RhoA activation to impact on pre-TCR–mediated signaling was in marked contrast to its actions on T cell responses mediated by the mature TCR α/β complex. Cells expressing active RhoA were thus hyperresponsive in the context of TCR-induced proliferation in vitro and in vivo showed augmented positive selection of thymocytes expressing defined TCR complexes. This reveals that RhoA function is not only important for pre-T cells but also plays a role in determining the fate of mature T cells.

scholarly journals Analysis of T-cell differentiation antigens in acute lymphatic leukemia using monoclonal antibodies

Blood ◽  
1982 ◽  
Vol 60 (3) ◽  
pp. 752-757 ◽  
Author(s):  
B Koziner ◽  
D Gebhard ◽  
T Denny ◽  
S McKenzie ◽  
BD Clarkson ◽  
...  
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
Cell Differentiation ◽  
T Cell ◽  
Cytotoxic T Cells ◽  
T Cell Differentiation ◽  
Leukemic Cells ◽  
Phenotypic Analysis ◽  
Lymphatic Leukemia ◽  
Normal Differentiation

Abstract Leukemic cells in 134 patients with ALL were analyzed by a panel of mouse monoclonal antibodies. Two antibodies are reactive with all peripheral blood T cells but define different surface antigens (Leu-1 and Leu-4). Two other antibodies react with antigens that are restricted to suppressor/cytotoxic T cells (Leu-2) and to helper T cells (Leu-3). We also used antibodies to the receptor for sheep red blood cells (SRBC) (Leu-5) and to a human “TL-like” antigen that is found on most thymocytes but not in peripheral T cells (Leu-6). An antibody to the human p29.34 “Ia-like” molecule was also tested. Of the 134 ALL patients, 17 had a predominance of SRBC-rosetting (Leu-5+) lymphoblasts (“T” ALL), expressing different surface phenotypes defined by this panel of monoclonal antibodies. These phenotypes were not readily classifiable according to a scheme of sequential stages of normal differentiation proposed. Moreover, the lymphoblasts in 8 of 113 patients not expressing conventional B- to T-cell markers (“null” ALL) reacted with the monoclonal anti-T-cell antibodies. This study suggests that the classification of lymphoblasts in ALL based on the reactivities observed with this panel of mouse monoclonal antibodies is not easily reconciled with current models of normal T-cell differentiation. However, it should be emphasized that the precise sequence of antigenic expression by cells undergoing thymic differentiation is still not fully known, and further phenotypic analysis of ALL cells might contribute to an improved understanding of this malignancy.

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