Generation of self-reactive, shared T-cell receptor α chains in the human thymus

Abstract Immune reconstitution is a critical component of recovery after treatment of human immunodeficiency virus (HIV) infection, cancer chemotherapy, and hematopoietic stem cell transplantation. The ability to enhance T-cell production would benefit such treatment. We examined the effects of exogenous interleukin-7 (IL-7) on apoptosis, proliferation, and the generation of T-cell receptor rearrangement excision circles (TRECs) in human thymus. Quantitative polymerase chain reaction demonstrated that the highest level of TRECs (14 692 copies/10 000 cells) was present in the CD1a+CD3−CD4+CD8+stage in native thymus, suggesting that TREC generation occurred following the cellular division in this subpopulation. In a thymic organ culture system, exogenous IL-7 increased the TREC frequency in fetal as well as infant thymus, indicating increased T-cell receptor (TCR) rearrangement. Although this increase could be due to the effect of IL-7 to increase thymocyte proliferation and decrease apoptosis of immature CD3− cells, the in vivo experiments using NOD/LtSz-scid mice given transplants of human fetal thymus and liver suggested that IL-7 can also directly enhance TREC generation. Our results provide compelling evidence that IL-7 has a direct effect on increasing TCR-αβ rearrangement and indicate the potential use of IL-7 for enhancing de novo naı̈ve T-cell generation in immunocompromised patients.

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T-cell receptor beta-chain gene rearrangement and expression during human thymic ontogenesis

Blood ◽

10.1182/blood.v79.6.1472.1472 ◽

1992 ◽

Vol 79 (6) ◽

pp. 1472-1483 ◽

Cited By ~ 19

Author(s):

A Bonati ◽

P Zanelli ◽

S Ferrari ◽

A Plebani ◽

B Starcich ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Chain Gene ◽

Gene Transcript ◽

Beta Chain ◽

Early Stages ◽

Human Thymus ◽

Nucleotide Insertions ◽

Beta Gene

Abstract T-cell receptor (TCR) beta-chain proteins appear early (approximately 15th week of gestation) during human thymic ontogenesis. These beta- chain proteins, which appear before terminal deoxynucleotidyl transferase (TdT), could be an expression of a fully rearranged (V-D- J), incompletely rearranged (D-J), or germline TCR beta-chain gene. The aims of this study, performed from the 15th week onward, were the following: (1) to investigate whether or not TCR beta gene rearranges at an early stage during human thymic ontogenesis; (2) to investigate whether complete presumptive functional (1.3 kb) TCR beta gene transcript is present at these early stages of development, or if incomplete (1 kb) or germ-line (1.1 kb) transcripts are expressed; (3) to examine the phenotype of TCR beta-chain+ cells with two-color fluorescence using monoclonal antibody (MoAb) beta F1 and MoAbs that recognize CD1, CD2, CD3, CD4, CD8, CD5, and CD7 antigens (rabbit anti- calf TdT antiserum was used to detect TdT); and (4) to demonstrate whether or not beta gene N-diversity regions are detectable as early as the 15th week and whether or not N-nucleotide insertions correlate to TdT expression. Fifteen- to 22-week fetal thymuses and pediatric thymuses were investigated. We demonstrated that TCR beta-chain gene rearranged as early as the 15th week in human thymus and that a complete functional TCR beta gene transcript was expressed at these early stages of human development. No other analyses to date have investigated TCR beta gene expression in early human thymus using molecular biology techniques. No significant differences were detectable between phenotypic analysis of fetal and pediatric samples, except for TdT expression, which appeared after the 20th week. Essentially all mCD3+ (OKT3+) cells were beta-chain+ at the different weeks investigated. A significant percentage of CD1+ cells were beta- chain+, and the percentage increased along with the age of development. After the 20th week, we identified three main populations: TdT+, cCD3+, beta F-(early thymic precursors); TdT+, CD1+, beta F1+ (intermediate maturity cortical thymocytes); and TdT-, mCD3+, beta F1++ (mature medullary thymocytes). Given these values, we may consider beta-chain expression an ordered process. beta gene N-nucleotide insertions were correlated to TdT expression, since N-regions increased considerably after the 20th week. A further increase of N-nucleotide insertions was detected from the 22nd week to the 32nd week.

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TiγA+δTCS1+ T cells in human thymus. Analysis of the T cell receptor

European Journal of Immunology ◽

10.1002/eji.1830220742 ◽

1992 ◽

Vol 22 (7) ◽

pp. 1947-1950 ◽

Cited By ~ 1

Author(s):

Roland Bosse ◽

Hans Heiken ◽

Waldemar Kolanus ◽

Patricia Delany ◽

Reinhold E. Schmidt ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Human Thymus

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Interferon-inducible protein 10, monokine induced by interferon gamma, and interferon-inducible T-cell alpha chemoattractant are produced by thymic epithelial cells and attract T-cell receptor (TCR) αβ+CD8+ single-positive T cells, TCRγδ+ T cells, and natural killer–type cells in human thymus

Blood ◽

10.1182/blood.v97.3.601 ◽

2001 ◽

Vol 97 (3) ◽

pp. 601-607 ◽

Cited By ~ 74

Author(s):

Paola Romagnani ◽

Francesco Annunziato ◽

Elena Lazzeri ◽

Lorenzo Cosmi ◽

Chiara Beltrame ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Natural Killer ◽

T Cell Receptor ◽

Interferon Gamma ◽

Cell Receptor ◽

Human Thymus ◽

Single Positive ◽

Inducible Protein ◽

Interferon Inducible Protein

Abstract Strong reactivity for interferon-inducible protein 10 (IP-10), monokine induced by interferon gamma (Mig), and interferon-inducible T-cell alpha chemoattractant (I-TAC) was found in epithelial cells mainly localized to the medulla of postnatal human thymus. The CXC chemokine receptor common to the 3 chemokines (CXCR3) was also preferentially expressed in medullary areas of the same thymuses and appeared to be a property of 4 distinct populations: CD3+T-cell receptor (TCR) αβ+CD8+ single-positive (SP) T cells, TCRγδ+ T cells, natural killer (NK)–type cells, and a small subset of CD3+(low)CD4+CD8+TCRαβ+double-positive (DP) T cells. IP-10, Mig, and I-TAC showed chemoattractant activity for TCRαβ+CD8+ SP T cells, TCRγδ+ T cells, and NK-type cells, suggesting their role in the migration of different subsets of mature thymocytes during human thymus lymphopoiesis.

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T-cell receptor beta-chain gene rearrangement and expression during human thymic ontogenesis

Blood ◽

10.1182/blood.v79.6.1472.bloodjournal7961472 ◽

1992 ◽

Vol 79 (6) ◽

pp. 1472-1483 ◽

Cited By ~ 1

Author(s):

A Bonati ◽

P Zanelli ◽

S Ferrari ◽

A Plebani ◽

B Starcich ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Chain Gene ◽

Gene Transcript ◽

Beta Chain ◽

Early Stages ◽

Human Thymus ◽

Nucleotide Insertions ◽

Beta Gene

T-cell receptor (TCR) beta-chain proteins appear early (approximately 15th week of gestation) during human thymic ontogenesis. These beta- chain proteins, which appear before terminal deoxynucleotidyl transferase (TdT), could be an expression of a fully rearranged (V-D- J), incompletely rearranged (D-J), or germline TCR beta-chain gene. The aims of this study, performed from the 15th week onward, were the following: (1) to investigate whether or not TCR beta gene rearranges at an early stage during human thymic ontogenesis; (2) to investigate whether complete presumptive functional (1.3 kb) TCR beta gene transcript is present at these early stages of development, or if incomplete (1 kb) or germ-line (1.1 kb) transcripts are expressed; (3) to examine the phenotype of TCR beta-chain+ cells with two-color fluorescence using monoclonal antibody (MoAb) beta F1 and MoAbs that recognize CD1, CD2, CD3, CD4, CD8, CD5, and CD7 antigens (rabbit anti- calf TdT antiserum was used to detect TdT); and (4) to demonstrate whether or not beta gene N-diversity regions are detectable as early as the 15th week and whether or not N-nucleotide insertions correlate to TdT expression. Fifteen- to 22-week fetal thymuses and pediatric thymuses were investigated. We demonstrated that TCR beta-chain gene rearranged as early as the 15th week in human thymus and that a complete functional TCR beta gene transcript was expressed at these early stages of human development. No other analyses to date have investigated TCR beta gene expression in early human thymus using molecular biology techniques. No significant differences were detectable between phenotypic analysis of fetal and pediatric samples, except for TdT expression, which appeared after the 20th week. Essentially all mCD3+ (OKT3+) cells were beta-chain+ at the different weeks investigated. A significant percentage of CD1+ cells were beta- chain+, and the percentage increased along with the age of development. After the 20th week, we identified three main populations: TdT+, cCD3+, beta F-(early thymic precursors); TdT+, CD1+, beta F1+ (intermediate maturity cortical thymocytes); and TdT-, mCD3+, beta F1++ (mature medullary thymocytes). Given these values, we may consider beta-chain expression an ordered process. beta gene N-nucleotide insertions were correlated to TdT expression, since N-regions increased considerably after the 20th week. A further increase of N-nucleotide insertions was detected from the 22nd week to the 32nd week.

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