Stimulated plasmacytoid dendritic cells impair human T-cell development

Abstract Thymocytes and thymic epithelial cell (TEC) cross-talk is crucial to preserve thymic architecture and function, including maturation of TECs and dendritic cells, and induction of mechanisms of central tolerance. We have analyzed thymic maturation and organization in 9 infants with various genetic defects leading to complete or partial block in T-cell development. Profound abnormalities of TEC differentiation (with lack of AIRE expression) and severe reduction of thymic dendritic cells were identified in patients with T-negative severe combined immunodeficiency, reticular dysgenesis, and Omenn syndrome. The latter also showed virtual absence of thymic Foxp3+ T cells. In contrast, an IL2RG-R222C hypomorphic mutation permissive for T-cell development allowed for TEC maturation, AIRE expression, and Foxp3+ T cells. Our data provide evidence that severe defects of thymopoiesis impinge on TEC homeostasis and may affect deletional and nondeletional mechanisms of central tolerance, thus favoring immune dysreactive manifestations, as in Omenn syndrome.

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Faculty Opinions recommendation of Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717996344.793474264 ◽

2013 ◽

Author(s):

Muriel Moser ◽

Oberdan Leo

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Regulatory T Cell ◽

T Cell Development ◽

Cell Development ◽

Thymic Medulla

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Human T cell development: Lessons from patients lacking MHC class II expression

Human Immunology ◽

10.1016/0198-8859(96)85288-8 ◽

1996 ◽

Vol 47 (1-2) ◽

pp. 109

Author(s):

Peter van den Elsen ◽

Judy Henwood ◽

Anette van Boxel-Dezaire ◽

Ron Schipper ◽

Martijn den Hoedt ◽

...

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

T Cell Development ◽

Class Ii ◽

Cell Development ◽

Human T Cell

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Development of a diverse human T-cell repertoire despite stringent restriction of hematopoietic clonality in the thymus

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1519118112 ◽

2015 ◽

Vol 112 (44) ◽

pp. E6020-E6027 ◽

Cited By ~ 22

Author(s):

Martijn H. Brugman ◽

Anna-Sophia Wiekmeijer ◽

Marja van Eggermond ◽

Ingrid Wolvers-Tettero ◽

Anton W. Langerak ◽

...

Keyword(s):

T Cell ◽

T Cell Development ◽

Xenograft Model ◽

Subsequent Development ◽

Cell Receptor ◽

Cell Development ◽

Cell Repertoire ◽

Hematopoietic Stem ◽

Human T Cell ◽

Hsc Transplantation

The fate and numbers of hematopoietic stem cells (HSC) and their progeny that seed the thymus constitute a fundamental question with important clinical implications. HSC transplantation is often complicated by limited T-cell reconstitution, especially when HSC from umbilical cord blood are used. Attempts to improve immune reconstitution have until now been unsuccessful, underscoring the need for better insight into thymic reconstitution. Here we made use of the NOD-SCID-IL-2Rγ−/− xenograft model and lentiviral cellular barcoding of human HSCs to study T-cell development in the thymus at a clonal level. Barcoded HSCs showed robust (>80% human chimerism) and reproducible myeloid and lymphoid engraftment, with T cells arising 12 wk after transplantation. A very limited number of HSC clones (<10) repopulated the xenografted thymus, with further restriction of the number of clones during subsequent development. Nevertheless, T-cell receptor rearrangements were polyclonal and showed a diverse repertoire, demonstrating that a multitude of T-lymphocyte clones can develop from a single HSC clone. Our data imply that intrathymic clonal fitness is important during T-cell development. As a consequence, immune incompetence after HSC transplantation is not related to the transplantation of limited numbers of HSC but to intrathymic events.

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A linkage between dendritic cell and T-cell development in the mouse thymus: the capacity of sequential T-cell precursors to form dendritic cells in culture

Developmental & Comparative Immunology ◽

10.1016/s0145-305x(98)00012-3 ◽

1998 ◽

Vol 22 (3) ◽

pp. 339-349 ◽

Cited By ~ 22

Author(s):

Karen Lucas ◽

David Vremec ◽

Li Wu ◽

Ken Shortman

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Dendritic Cell ◽

T Cell Development ◽

Cell Development ◽

Mouse Thymus ◽

Cells In Culture

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LMO2 and TAL1 Cooperate in a Model of Human T−Cell Leukemogenesis.

Blood ◽

10.1182/blood.v108.11.773.773 ◽

2006 ◽

Vol 108 (11) ◽

pp. 773-773

Author(s):

James A. Kennedy ◽

Frederic Barabe ◽

John E. Dick

Keyword(s):

T Cell ◽

T Cell Development ◽

Cell Development ◽

Early Event ◽

Aberrant Expression ◽

Human T Cell ◽

Differentiation Block ◽

Population Doublings ◽

T Cell Leukemogenesis ◽

T Lymphopoiesis

Abstract T−cell acute lymphoblastic leukemia (T−ALL) is associated with the aberrant expression of a limited number of genes, including the basic helix−loop−helix transcription factor TAL1 (SCL) and the LIM−only domain gene LMO2, in the T−cell lineage. These proteins are thought to mediate their leukemogenic effects by interfering with the transcriptional programs that regulate differentiation during normal thymocyte development. The recent X−linked SCID gene therapy trial has highlighted a role for LMO2 overexpression as an early event in T−lineage leukemogenesis, as retroviral integration into the LMO2 locus was detected in multiple patients that went on to develop T−ALL. However, our understanding of the effects of aberrant LMO2 expression upon human T−lymphopoiesis is currently limited. In order to address this area, lineage−depleted human umbilical cord blood cells were transduced with a lentivirus encoding LMO2 or a control virus, then seeded upon OP9−DL1 stroma. As expected, control cells underwent a normal stage−specific program of T cell development concluding with the emergence of a population of CD4+CD8+CD3hi TCRαβ+ cells. Interestingly, LMO2−expressing cells exhibited a differentiation block at the double negative (DN: CD8−CD4−CD7+) stage of T−cell development. These LMO2−expressing DN cells had a growth advantage compared to control cells (23 population doublings over 75 days for LMO2 vs. 15 p.d. over 60 days for control) but were not immortalized as they stopped expanding after 75 days of co−culture. In the context of T−cell leukemogenesis, these findings suggest that as an initial hit, LMO2 overexpression can induce a blockage in differentiation, resulting in the generation of a proliferative pre−leukemic pool of DN cells. These cells could subsequently accumulate additional mutations leading to the eventual development of an overt leukemia. Given that TAL1 has been shown to accelerate the development of leukemia in LMO2 transgenic mice, and that these two genes are simultaneously overexpressed in a significant percentage of T−ALL cases, this oncogene was an ideal candidate for a second genetic hit. Thus, a retrovirus encoding TAL1 was utilized to infect the LMO2+ DN T−cell population. The expression of TAL1 in these cells significantly increased their proliferative capacity and greatly extended their lifespan, as greater than 60 population doublings occurred over 220 days of culture on stroma. Of note, TAL−1 overexpression appeared to release the LMO2−induced differentiation block at the DN stage, resulting in the emergence of a population of CD4+CD8+CD3− lymphoblasts. Taken together, these findings describe the first experimental model that studies the early stages of human T−cell leukemogenesis by starting with the physiologically relevant population of primitive primary human hematopoietic cells and analyzing the impact of sequential genetic hits upon T−lymphopoiesis. These data indicate that the aberrant expression of LMO2 contributes to leukemogenesis as an early event by generating a pre−leukemic pool of DN cells and that TAL−1 overexpression in this population acts a cooperating event that leads to the emergence of a highly proliferative, immortalized clone. Given that an experimentally induced leukemia model requires the demonstration of in vivo disease, studies assessing the leukemic potential of human cells co−expressing TAL1 and LMO2 are underway in a novel NOD/SCID system that supports human T cell development.

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TECK: A Novel CC Chemokine Specifically Expressed by Thymic Dendritic Cells and Potentially Involved in T Cell Development

Immunity ◽

10.1016/s1074-7613(00)80531-2 ◽

1997 ◽

Vol 7 (2) ◽

pp. 291-301 ◽

Cited By ~ 216

Author(s):

Alain P Vicari ◽

David J Figueroa ◽

Joseph A Hedrick ◽

Jessica S Foster ◽

Komal P Singh ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

T Cell Development ◽

Cell Development ◽

Cc Chemokine

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In Vitro Models of Human T Cell Development: Dishing Out Progenitor T Cells

Current Immunology Reviews ◽

10.2174/157339507779802205 ◽

2007 ◽

Vol 3 (1) ◽

pp. 57-75 ◽

Cited By ~ 2

Author(s):

Ross La Motte-Mohs ◽

Geneve Awong ◽

Juan Carlos Zuniga-Pflucker

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Development ◽

Cell Development ◽

In Vitro Models ◽

Human T Cell

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Early human T cell development: analysis of the human thymus at the time of initial entry of hematopoietic stem cells into the fetal thymic microenvironment.

Journal of Experimental Medicine ◽

10.1084/jem.181.4.1445 ◽

1995 ◽

Vol 181 (4) ◽

pp. 1445-1458 ◽

Cited By ~ 96

Author(s):

B F Haynes ◽

C S Heinly

Keyword(s):

Stem Cells ◽

T Cell ◽

Hematopoietic Stem Cells ◽

T Cell Development ◽

Fold Increase ◽

Cell Receptor ◽

Cell Development ◽

Hematopoietic Stem ◽

Human Thymus ◽

Human T Cell

To determine events that transpire during the earliest stages of human T cell development, we have studied fetal tissues before (7 wk), during (8.2 wk), and after (9.5 wk to birth) colonization of the fetal thymic rudiment with hematopoietic stem cells. Calculation of the approximate volumes of the 7- and 8.2-wk thymuses revealed a 35-fold increase in thymic volumes during this time, with 7-wk thymus height of 160 microM and volume of 0.008 mm3, and 8.2-wk thymus height of 1044 microM and volume of 0.296 mm3. Human thymocytes in the 8.2-wk thymus were CD4+ CD8 alpha+ and cytoplasmic CD3 epsilon+ cCD3 delta+ CD8 beta- and CD3 zetta-. Only 5% of 8-wk thymocytes were T cell receptor (TCR)-beta+, < 0.1% were TCR-gamma+, and none reacted with monoclonal antibodies against TCR-delta. During the first 16 wk of gestation, we observed developmentally regulated expression of CD2 and CD8 beta (appearing at 9.5 wk), CD1a,b, and c molecules (CD1b, then CD1c, then CD1a), TCR molecules (TCR-beta, then TCR-delta), CD45RA and CD45RO isoforms, CD28 (10 wk), CD3 zeta (12-13 wk), and CD6 (12,75 wk). Whereas CD2 was not expressed at the time of initiation of thymic lymphopoiesis, a second CD58 ligand, CD48, was expressed at 8.2 wk, suggesting a role for CD48 early in thymic development. Taken together, these data define sequential phenotypic and morphologic changes that occur in human thymus coincident with thymus colonization by hematopoietic stem cells and provide insight into the molecules that are involved in the earliest stages of human T cell development.

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