scholarly journals Early defects in human T-cell development severely affect distribution and maturation of thymic stromal cells: possible implications for the pathophysiology of Omenn syndrome

Blood ◽  
2009 ◽  
Vol 114 (1) ◽  
pp. 105-108 ◽  
Author(s):  
Pietro Luigi Poliani ◽  
Fabio Facchetti ◽  
Maria Ravanini ◽  
Andrew Richard Gennery ◽  
Anna Villa ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Severe Combined Immunodeficiency ◽  
T Cell Development ◽  
Cell Development ◽  
Thymic Epithelial Cell ◽  
Omenn Syndrome ◽  
Central Tolerance ◽  
Human T Cell

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.

scholarly journals Thymic Epithelial Cell-Derived IL-15 and IL-15 Receptor α Chain Foster Local Environment for Type 1 Innate Like T Cell Development

2021 ◽  
Vol 12 ◽  
Author(s):  
Huishan Tao ◽  
Lei Li ◽  
Nan-Shih Liao ◽  
Kimberly S. Schluns ◽  
Shirley Luckhart ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Local Environment ◽  
Cell Development ◽  
Thymic Epithelial Cells ◽  
Thymic Epithelial Cell ◽  
Central Tolerance ◽  
Selection Of

Expression of tissue-restricted antigens (TRAs) in thymic epithelial cells (TECs) ensures negative selection of highly self-reactive T cells to establish central tolerance. Whether some of these TRAs could exert their canonical biological functions to shape thymic environment to regulate T cell development is unclear. Analyses of publicly available databases have revealed expression of transcripts at various levels of many cytokines and cytokine receptors such as IL-15, IL-15Rα, IL-13, and IL-23a in both human and mouse TECs. Ablation of either IL-15 or IL-15Rα in TECs selectively impairs type 1 innate like T cell, such as iNKT1 and γδT1 cell, development in the thymus, indicating that TECs not only serve as an important source of IL-15 but also trans-present IL-15 to ensure type 1 innate like T cell development. Because type 1 innate like T cells are proinflammatory, our data suggest the possibility that TEC may intrinsically control thymic inflammatory innate like T cells to influence thymic environment.

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

2007 ◽  
Vol 3 (1) ◽  
pp. 57-75 ◽  
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

scholarly journals Interleukin-7 is a critical growth factor in early human T-cell development

Blood ◽  
1996 ◽  
Vol 88 (11) ◽  
pp. 4239-4245 ◽  
Author(s):  
J Plum ◽  
M De Smedt ◽  
G Leclercq ◽  
B Verhasselt ◽  
B Vandekerckhove
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Molecular Defect ◽  
Gamma Chain ◽  
Alpha Chain ◽  
Interleukin 7 ◽  
Human T Cell ◽  
Early Human

Highly purified human CD34+ fetal liver stem cells differentiate to mature T cells when seeded in vitro into isolated fetal thymic lobes of severe combined immunodeficient (SCID) mice followed by fetal thymus organ culture (FTOC). Here, this chimeric human-mouse FTOC was used to address the role of interleukin-7 (IL-7) and of the alpha chain of the IL-7 receptor (IL-7R alpha) in early human T-cell development. We report that addition of either the monoclonal antibody (MoAb) M25, which neutralizes both human and mouse IL-7, or the MoAb M21, which recognizes and blocks exclusively the human high-affinity alpha-chain of the IL-7R, results in a profound reduction in human thymic cellularity. Analysis of lymphoid subpopulations indicates that a highly reduced number of cells undergo maturation from CD34+ precursor cells toward CD4+CD3-CD1+ progenitor cells and subsequently toward CD4+CD8+ thymocytes. Our results reveal a critical role for IL-7 during early human thymocyte development, and may explain the absence or highly reduced levels of T cells in patients with X-linked SCID. The molecular defect in these patients has been shown to be a mutation in the gamma chain of the IL-2R. Although this gamma chain is not only present in the IL-2R, but also forms an essential part of other cytokine receptors, including IL-4, IL-7, IL-9, IL-13, and IL-15, the T- cell defect in these patients can be explained by the fact that IL-7 is not able to transduce its signal by the molecular defect of the common gamma (gamma c) chain and that IL-7 is indispensable for T-cell development.

A partial deficiency of interleukin-7Rα is sufficient to abrogate T-cell development and cause severe combined immunodeficiency

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2803-2807 ◽  
Author(s):  
Chaim M. Roifman ◽  
Junyan Zhang ◽  
David Chitayat ◽  
Nigel Sharfe
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Clinical Presentation ◽  
Severe Combined Immunodeficiency ◽  
T Cell Development ◽  
Cell Development ◽  
Combined Immunodeficiency ◽  
Cell Numbers ◽  
Partial Deficiency

Abstract Both in vitro and in vivo studies established that interleukin 7 (IL-7) is essential for differentiation of immature T cells and B cells but not natural killer (NK) cells in the mouse. In humans, although both T-cell and B-cell progenitors express the functional IL-7 receptor that consists of IL-7Rα and the γcommon (γc) chain, this lymphocyte receptor system is critical for T lineage but not for B lineage development. Indeed, complete γc deficiency like IL-7Rα deficiency results in the arrest of T-cell but not B-cell development (T−B+ SCID). However, partial deficiency of γc caused by missense mutations results in a T+B+ phenotype and a delay of clinical presentation. It was therefore plausible to assume that partial deficiency of IL-7Rα, like partial γc deficiency may lead to a milder clinical and immunologic phenotype. A P132S mutation in the IL-7Rα was identified in 3 patients with severe combined immunodeficiency (SCID) within an extensively consanguineous family. Substitution of proline with serine in the extracellular portion of IL-7Rα did not affect IL-7Rα messenger RNA (mRNA) and protein expression, but severely compromised affinity to IL-7, resulting in defective signal transduction. In response to IL-7 stimulation, Jak-3 phosphorylation was markedly reduced in both patient cells as well as in COS cells reconstituted with mutant IL-7Rα. Surprisingly, this partial deficiency of IL-7Rα resulted in a severe phenotype, including markedly reduced circulating T cells while sparing B-cell numbers similar to γc chain deficiency. However, unlike the previously reported cases, serum immunoglobulins were virtually absent. Further, unlike γc deficiency, NK cell numbers and function was preserved. Despite the partial deficiency, clinical presentation was indistinguishable from a complete γc deficiency, including severe and persistent viral and protozoal infections and failure to thrive. Unlike partial γc deficiency, a partial deficiency of IL-7Rα results in an arrest of T-cell development, leading to typical severe combined immunodeficiency. This underscores the critical role of IL-7Rα chain in the differentiation of T cells.

KLF4 Acts As a Tumor Suppressor in T-Acute Lymphoblastic Leukemia and Negatively Regulates Human T Cell Development and Homeostasis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2405-2405
Author(s):  
Bing Xu ◽  
Peng Li
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Cell Development ◽  
Dependent Manner ◽  
Human T Cell

Abstract The transcription factor Kruppel-like factor 4 (KLF4) may induce tumorigenesis or suppress tumor growth in a tissue-dependent manner. We found that overexpression of KLF4 induced not only human acute T-acute lymphoblastic leukemia (T-ALL) cell lines but also primary samples from T-ALL patients to undergo apoptosis through the BCL2/BCLXL pathway in vitro. T cell-associated genes including BCL11B, GATA3, and TCF7 were negatively regulated by KLF4 overexpression. Especially, KLF4 induced SUMOylation and degradation of BCL11B. However, the KLF4-induced apoptosis in T-ALL was rescued by the in vivo microenvironment. Furthermore, the invasion capacity of T-ALL to hosts was compromised when KLF4 was overexpressed. In normal human T cells, the overexpression of KLF4 severely impaired T cell development at early stages, but the blockage of T cell development was resumed by restoration of GATA3 or ICN1. In summary, our data demonstrate that KLF4 acts as a tumor suppressor in malignant T cells and that downregulation of KLF4 may be a prerequisite for early human T cell development and homeostasis. Disclosures No relevant conflicts of interest to declare.

scholarly journals Requirement of dendritic cells and B cells in the clonal deletion of Mls-reactive T cells in the thymus.

1991 ◽  
Vol 173 (3) ◽  
pp. 539-547 ◽  
Author(s):  
O Mazda ◽  
Y Watanabe ◽  
J Gyotoku ◽  
Y Katsura
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Clonal Deletion ◽  
Fetal Thymus ◽  
Effector Cells

The present study was performed to identify cells responsible for the elimination of T cells reactive with minor lymphocyte-stimulating (Mls) antigens during T cell development. Experiments were carried out in a fetal thymus organ culture (FTOC) system. To examine the tolerance-inducing activity, various populations of cells from adult CBA/J (Mls-1a) mice were injected into deoxyguanosine (dGuo)-treated FTOC of C3H/He (Mls-1b) mice with a microinjector, and 2 d later, the thymus lobes were injected with fetal thymus cells from C3H/He mice as T cell precursors. After 14 d of cultivation, cells were harvested and assayed for the expression of the T cell receptor V beta 6 element. The absence or marked reduction of T cells expressing V beta 6 at high levels (V beta 6high) was regarded as indicating the deletion of Mls-1a-reactive T cells. T cell-depleted populations of thymic as well as splenic cells from CBA/J mice were able to induce clonal deletion. Further characterization of the effector cells was carried out by fractionating the spleen cells before injecting them into dGuo-FTOC. None of the dish-adherent population, dish-nonadherent population, or purified B cells alone were able to induce clonal deletion, whereas the addition of purified B cells to adherent cells restored tolerance inducibility. It was further shown that a combination of CBA/J B cells and C3H/He dendritic cells was effective in eliminating Mls-reactive clones. These results indicate that for the deletion of clones reactive with Mls antigens during T cell development in the thymus, both DC and B cells are required.

Functional Role of Interleukin-4 (IL-4) and IL-7 in the Development of X-Linked Severe Combined Immunodeficiency

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 607-612 ◽  
Author(s):  
Satoru Kumaki ◽  
Naoto Ishii ◽  
Masayoshi Minegishi ◽  
Shigeru Tsuchiya ◽  
David Cosman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Severe Combined Immunodeficiency ◽  
T Cell Development ◽  
Interleukin 2 ◽  
Cell Development ◽  
Interleukin 4 ◽  
Combined Immunodeficiency ◽  
Survival Signal

X-linked severe combined immunodeficiency (X-SCID) is characterized by an absent or diminished number of T cells and natural-killer (NK) cells with a normal or elevated number of B cells, and results from mutations of the γc chain. The γc chain is shared by interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15 receptors. Recently, a survival signal through the IL-7 receptor  (IL-7R) chain was shown to be important for T-cell development in mice and was suggested to contribute to the X-SCID phenotype. In the present study, we examined function of a mutant γc chain (A156V) isolated from an X-SCID patient and found that T cells expressing the mutant γc chain were selectively impaired in their responses to IL-4 or IL-7 compared with the wild-type γc chain expressing cells although responses to IL-2 or IL-15 were relatively maintained. The result shows that IL-4– and/or IL-7–induced signaling through the γc chain is critical for T-cell development and plays an important role in the development of the X-SCID phenotype.

scholarly journals Stimulated plasmacytoid dendritic cells impair human T-cell development

Blood ◽  
2006 ◽  
Vol 108 (12) ◽  
pp. 3792-3800 ◽  
Author(s):  
H. Schmidlin ◽  
W. Dontje ◽  
F. Groot ◽  
S. J. Ligthart ◽  
A. D. Colantonio ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Plasmacytoid Dendritic Cells ◽  
Human T Cell

scholarly journals Interleukin-7 is a critical growth factor in early human T-cell development

Blood ◽  
1996 ◽  
Vol 88 (11) ◽  
pp. 4239-4245 ◽  
Author(s):  
J Plum ◽  
M De Smedt ◽  
G Leclercq ◽  
B Verhasselt ◽  
B Vandekerckhove
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Molecular Defect ◽  
Gamma Chain ◽  
Alpha Chain ◽  
Interleukin 7 ◽  
Human T Cell ◽  
Early Human

Abstract Highly purified human CD34+ fetal liver stem cells differentiate to mature T cells when seeded in vitro into isolated fetal thymic lobes of severe combined immunodeficient (SCID) mice followed by fetal thymus organ culture (FTOC). Here, this chimeric human-mouse FTOC was used to address the role of interleukin-7 (IL-7) and of the alpha chain of the IL-7 receptor (IL-7R alpha) in early human T-cell development. We report that addition of either the monoclonal antibody (MoAb) M25, which neutralizes both human and mouse IL-7, or the MoAb M21, which recognizes and blocks exclusively the human high-affinity alpha-chain of the IL-7R, results in a profound reduction in human thymic cellularity. Analysis of lymphoid subpopulations indicates that a highly reduced number of cells undergo maturation from CD34+ precursor cells toward CD4+CD3-CD1+ progenitor cells and subsequently toward CD4+CD8+ thymocytes. Our results reveal a critical role for IL-7 during early human thymocyte development, and may explain the absence or highly reduced levels of T cells in patients with X-linked SCID. The molecular defect in these patients has been shown to be a mutation in the gamma chain of the IL-2R. Although this gamma chain is not only present in the IL-2R, but also forms an essential part of other cytokine receptors, including IL-4, IL-7, IL-9, IL-13, and IL-15, the T- cell defect in these patients can be explained by the fact that IL-7 is not able to transduce its signal by the molecular defect of the common gamma (gamma c) chain and that IL-7 is indispensable for T-cell development.

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