Thymopoiesis and T Cell Development in Common Gamma Chain-Deficient Dogs

During the development of functional T lymphocytes, a variety of genes involved in antigen recognition undergo somatic rearrangement. These include the alpha, beta, and gamma chain genes. Recently a fourth rearranging gene, the delta chain gene, embedded in the alpha chain locus, has been described. We have determined the structure of the beta, gamma, and delta chain genes in 15 cases of T-cell acute lymphoblastic leukemia (T-ALL) representing stage I (CD7+, CD1-, CD3-) and stage II (CD7+, CD1+, CD3-) of intrathymic T-cell development. The alpha-delta locus was rearranged in 14 of the 15 cases. In three cases the delta constant region was deleted on both chromosomes, suggesting biallelic V-J alpha rearrangement. A limited pattern of rearrangement of the delta locus was observed in the remaining 11 cases. When the alpha-delta region was rearranged, there was rearrangement of the beta and gamma TcR in all cases except two; in these cases the beta chain was in the germline configuration. These findings support the hypothesis that delta chain gene rearrangement is an early event in T- cell development, possibly contemporary to gamma gene rearrangement, and that the delta locus has a limited repertoire.

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

Blood ◽

10.1182/blood.v88.11.4239.bloodjournal88114239 ◽

1996 ◽

Vol 88 (11) ◽

pp. 4239-4245 ◽

Cited By ~ 104

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.

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

Blood ◽

10.1182/blood.v88.11.4239.4239 ◽

1996 ◽

Vol 88 (11) ◽

pp. 4239-4245 ◽

Cited By ~ 5

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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Normal T cell development is possible without ‘functional’ gamma chain genes.

The EMBO Journal ◽

10.1002/j.1460-2075.1986.tb04400.x ◽

1986 ◽

Vol 5 (7) ◽

pp. 1589-1593 ◽

Cited By ~ 36

Author(s):

A. Traunecker ◽

F. Oliveri ◽

N. Allen ◽

K. Karjalainen

Keyword(s):

T Cell ◽

T Cell Development ◽

Cell Development ◽

Gamma Chain

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T-cell receptor delta gene rearrangement in childhood T-cell acute lymphoblastic leukemia

Blood ◽

10.1182/blood.v73.8.2133.2133 ◽

1989 ◽

Vol 73 (8) ◽

pp. 2133-2138 ◽

Cited By ~ 19

Author(s):

A Biondi ◽

E Champagne ◽

V Rossi ◽

G Giudici ◽

A Cantu-Rajnoldi ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Gene Rearrangement ◽

Lymphoblastic Leukemia ◽

T Cell Development ◽

Cell Development ◽

Early Event ◽

Chain Gene ◽

Gamma Chain ◽

Cell Acute Lymphoblastic Leukemia

Abstract During the development of functional T lymphocytes, a variety of genes involved in antigen recognition undergo somatic rearrangement. These include the alpha, beta, and gamma chain genes. Recently a fourth rearranging gene, the delta chain gene, embedded in the alpha chain locus, has been described. We have determined the structure of the beta, gamma, and delta chain genes in 15 cases of T-cell acute lymphoblastic leukemia (T-ALL) representing stage I (CD7+, CD1-, CD3-) and stage II (CD7+, CD1+, CD3-) of intrathymic T-cell development. The alpha-delta locus was rearranged in 14 of the 15 cases. In three cases the delta constant region was deleted on both chromosomes, suggesting biallelic V-J alpha rearrangement. A limited pattern of rearrangement of the delta locus was observed in the remaining 11 cases. When the alpha-delta region was rearranged, there was rearrangement of the beta and gamma TcR in all cases except two; in these cases the beta chain was in the germline configuration. These findings support the hypothesis that delta chain gene rearrangement is an early event in T- cell development, possibly contemporary to gamma gene rearrangement, and that the delta locus has a limited repertoire.

Download Full-text