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

Abstract 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.

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.

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.

scholarly journals Absence of interleukin 2 production in a severe combined immunodeficiency disease syndrome with T cells.

1990 ◽  
Vol 171 (5) ◽  
pp. 1697-1704 ◽  
Author(s):  
J P DiSanto ◽  
C A Keever ◽  
T N Small ◽  
G L Nicols ◽  
R J O'Reilly ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Severe Combined Immunodeficiency ◽  
T Cell Development ◽  
Interleukin 2 ◽  
Combined Immunodeficiency ◽  
Alternative Pathways ◽  
Immunodeficiency Disease ◽  
Severe Combined Immunodeficiency Disease ◽  
Subtle Abnormality

We have characterized a child with a severe combined immunodeficiency disease syndrome with increased numbers, but a normal distribution, of CD3+ T cells. This patient's immunological defect appears to be attributable to a selective deficiency in T cell production of IL-2, which may reflect a subtle abnormality in the IL-2 gene locus or a defect in a regulatory factor necessary for IL-2 transcription. The increased numbers of phenotypically normal T cells in this patient suggest that alternative pathways of T cell development exist in man or that IL-2 production intra- and extrathymically is controlled via distinct regulatory mechanisms.

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

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.

A Hypomorphic Cbfb Allele Reveals a Critical Dosage-Sensitive Function of Core Binding Factors at the Earliest Stages of T Cell Development.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 124-124
Author(s):  
Ivan Maillard ◽  
Laleh Talebian ◽  
Zhe Li ◽  
Yalin Guo ◽  
Daisuke Sugiyama ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dna Binding ◽  
B Cell ◽  
Bone Marrow Cells ◽  
T Cell Development ◽  
Cell Development ◽  
B Cell Development ◽  
Hematopoietic Stem

Abstract The family of core binding factors includes the DNA-binding subunits Runx1-3 and the common non-DNA binding partner CBFβ. Runx1 and CBFβ are essential for the emergence of hematopoietic stem cells during fetal development, but not for stem cell maintenance during later ontogeny. Runx1 is also required for megakaryocyte differentiation, B cell development, and for the DN2 to DN3 transition in thymocyte development. Runx2/CBFβ are critical for normal osteogenesis, and Runx3 for CD4 silencing in CD8+ T cells, but their contribution to other steps of hematopoietic development is unknown. To examine the collective role of core binding factors in hematopoiesis, we generated a hypomorphic Cbfb allele (Cbfbrss). CBFβ protein levels were reduced by approximately 2–3 fold in fetuses homozygous for the Cbfbrss allele (Cbfbrss/rss), and 3–4 fold in fetuses carrying one hypomorphic and one knockout allele (Cbfbrss/−). Cbfbrss/rss and Cbfbrss/− fetuses had normal erythroid and B cell development, and relatively mild abnormalities in megakaryocyte and granulocyte differentiation. In contrast, T cell development was very sensitive to an incremental reduction of CBFβ levels: mature thymocytes were decreased in Cbfbrss/rss fetuses, and virtually absent in Cbfbrss/−fetuses. We next assessed the development of Cbfbrss/rss and Cbfbrss/− fetal liver progenitors after transplantation to irradiated adult recipients, in competition with wild-type (wt) bone marrow cells. Wt, Cbfbrss/rss and Cbfbrss/− fetal progenitors replenished the erythroid, myeloid and B cell compartments equally well. The overall development of Cbfbrss/rss T cells was preserved, although CD4 expression was derepressed in double negative thymocytes. In Cbfbrss/− chimeras, mature thymocytes were entirely derived from competitor cells. Furthermore, the developmental block in Cbfbrss/− progenitors was present at the earliest stages of T cell development within the DN1 (ETP) and DN2 subsets. Our data define a critical CBFβ threshold for normal T cell development, and they situate an essential role of core binding factors during the earliest stages of T cell development. In addition, early thymopoiesis appeared more severely affected by reduced CBFβ dosage than by the lack of Runx1 (Ichikawa et al., Nat Med 2004; Growney et al., Blood 2005), suggesting that Runx2/3 may contribute to core binding factor activity in the T cell lineage.

An Essential Role of the RNA Editing Enzyme ADAR1 in T Cell Development.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 917-917
Author(s):  
Richard XuFeng ◽  
Qiong Yang ◽  
Youzhong Yuan ◽  
Binfeng Lu ◽  
Tao Cheng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Rna Editing ◽  
T Cell Receptor ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
T Cell Differentiation ◽  
Editing Enzyme

Abstract Abstract 917 Post-transcriptional regulation such as RNA editing in hematopoiesis and lymphopoiesis is poorly understood. ADAR1 (adenosine deaminase acting on RNA-1) is a RNA editing enzyme essential for embryonic development. Disruption of the ADAR1 gene was shown to cause defective embryonic hematopoiesis (Wang Q et al, Science 2000). Moreover, we have recently obtained direct evidence for the preferential effect of ADAR1 deletion on adult hematopoietic progenitor cells as opposed to the more primitive cells via a RNA-editing dependent mechanism by different conditional gene deletion strategies (Xufeng R et al PNAS 2009, in press). To further determine the role of ADAR1 in T cell development, we generated a mouse model in which ADAR1 was deleted specifically in T lymphocytes by interbreeding ADAR1lox/lox mice with Lck-Cre transgenic mice. In our current study, we report that ADAR1 is essential for T cell differentiation at the late progenitor stage in the thymus, coincident with T cell receptor-α/β expression. In ADAR1lox/loxLck-Cre mice, mature T cells decreased dramatically in peripheral blood, spleen and lymph nodes in comparison to littermate controls. In the thymus, the production of CD4+/CD8+ double positive cells was severely impaired and massive cell death was observed in pre-T cell populations. Within the pro-T cells, ADAR1 deletion resulted in a significant decrease of late progenitor cells but not early progenitor subsets. In both pro-T and pre-T cell stages, defective T cell development preferentially occurred in the beta chain positive cells, but was not apparent in gamma/delta T cells. Our data demonstrated an indispensable role of ADAR1 in early T cell differentiation that correlated with T cell receptor beta chain expression, thereby indicating that RNA editing by ADAR1 is an essential event in T cell development. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Noncanonical Wnt signaling promotes apoptosis in thymocyte development

2007 ◽  
Vol 204 (13) ◽  
pp. 3077-3084 ◽  
Author(s):  
Huiling Liang ◽  
Andrew H. Coles ◽  
Zhiqing Zhu ◽  
Jennifer Zayas ◽  
Roland Jurecic ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Wnt Signaling ◽  
T Cell Development ◽  
Cell Development ◽  
Thymocyte Development ◽  
Growth And Survival ◽  
Canonical Wnt

The Wnt–β-catenin signaling pathway has been shown to govern T cell development by regulating the growth and survival of progenitor T cells and immature thymocytes. We explore the role of noncanonical, Wnt–Ca2+ signaling in fetal T cell development by analyzing mice deficient for Wnt5a. Our findings reveal that Wnt5a produced in the thymic stromal epithelium does not alter the development of progenitor thymocytes, but regulates the survival of αβ lineage thymocytes. Loss of Wnt5a down-regulates Bax expression, promotes Bcl-2 expression, and inhibits apoptosis of CD4+CD8+ thymocytes, whereas exogenous Wnt5a increases apoptosis of fetal thymocytes in culture. Furthermore, Wnt5a overexpression increases apoptosis in T cells in vitro and increases protein kinase C (PKC) and calmodulin-dependent kinase II (CamKII) activity while inhibiting β-catenin expression and activity. Conversely, Wnt5a deficiency results in the inhibition of PKC activation, decreased CamKII activity, and elevation of β-catenin amounts in thymocytes. These results indicate that Wnt5a induction of the noncanonical Wnt–Ca2+ pathway alters canonical Wnt signaling and is critical for normal T cell development.

scholarly journals Bad Can Act as a Key Regulator of  T Cell Apoptosis and T Cell Development

1999 ◽  
Vol 189 (3) ◽  
pp. 575-586 ◽  
Author(s):  
Chen-Lang Mok ◽  
Gabriel Gil-Gómez ◽  
Owen Williams ◽  
Mark Coles ◽  
Samir Taga ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Apoptosis ◽  
Cell Cycle Progression ◽  
Cell Activation ◽  
T Cell Development ◽  
Interleukin 2 ◽  
Cell Development ◽  
T Cell Apoptosis

Bad is a distant relative of Bcl-2 and acts to promote cell death. Here, we show that Bad expression levels are greatly increased in thymocytes during apoptosis. We generated bad transgenic mice to study the action of upregulated Bad expression on T cell apoptosis. The T cells from these mice are highly sensitive to apoptotic stimuli, including anti-CD95. The numbers of T cells are greatly depleted and the processes of T cell development and selection are perturbed. We show that the proapoptotic function of Bad in primary T cells is regulated by Akt kinase and that Bad overexpression enhances both cell cycle progression and interleukin 2 production after T cell activation. These data suggest that Bad can act as a key regulator of T cell apoptosis and that this is a consequence of its upregulation after exposure to death stimuli.

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