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Quantitative impact of thymic clonal deletion on the T cell repertoire.

van Meerwijk JP, Marguerat S, Lees RK, Germain RN, Fowlkes BJ, MacDonald HR - J. Exp. Med. (1997)

Bottom Line: Interactions between major histocompatibility complex (MHC) molecules expressed on stromal cells and antigen-specific receptors on T cells shape the repertoire of mature T lymphocytes emerging from the thymus.The quantitative impact of negative selection on the potentially available repertoire is currently unknown.To address this issue, we have constructed radiation bone marrow chimeras in which MHC molecules are present on radioresistant thymic epithelial cells (to allow positive selection) but absent from radiosensitive hematopoietic elements responsible for negative selection.

View Article: PubMed Central - PubMed

Affiliation: Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.

ABSTRACT
Interactions between major histocompatibility complex (MHC) molecules expressed on stromal cells and antigen-specific receptors on T cells shape the repertoire of mature T lymphocytes emerging from the thymus. Some thymocytes with appropriate receptors are stimulated to undergo differentiation to the fully mature state (positive selection), whereas others with strongly autoreactive receptors are triggered to undergo programmed cell death before completing this differentiation process (negative selection). The quantitative impact of negative selection on the potentially available repertoire is currently unknown. To address this issue, we have constructed radiation bone marrow chimeras in which MHC molecules are present on radioresistant thymic epithelial cells (to allow positive selection) but absent from radiosensitive hematopoietic elements responsible for negative selection. In such chimeras, the number of mature thymocytes was increased by twofold as compared with appropriate control chimeras This increase in steady-state numbers of mature thymocytes was not related to proliferation, increased retention, or recirculation and was accompanied by a similar two- to threefold increase in the de novo rate of generation of mature cells. Taken together, our data indicate that half to two-thirds of the thymocytes able to undergo positive selection die before full maturation due to negative selection.

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Related in: MedlinePlus

Accelerated kinetics of generation of CD4SP and CD8SP  thymocytes in wild-type hosts lacking MHC class II or I, respectively, on  hematopoietic elements. 6-wk-old wt→ wt (n = 3, day 9; n = 6, days 10– 13), MHC I°II°→ wt (n = 3 each day), and MHC I°→ wt (n = 3) chimeras were sublethally irradiated (720 rads) and analyzed on day 9–13 as in  Fig. 2. Data represent average percentage of CD4+CD8−TCRhigh and  CD4−CD8+TCRhigh thymocytes ± SD.
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Figure 4: Accelerated kinetics of generation of CD4SP and CD8SP thymocytes in wild-type hosts lacking MHC class II or I, respectively, on hematopoietic elements. 6-wk-old wt→ wt (n = 3, day 9; n = 6, days 10– 13), MHC I°II°→ wt (n = 3 each day), and MHC I°→ wt (n = 3) chimeras were sublethally irradiated (720 rads) and analyzed on day 9–13 as in Fig. 2. Data represent average percentage of CD4+CD8−TCRhigh and CD4−CD8+TCRhigh thymocytes ± SD.

Mentions: Single-cell suspensions of thymocytes were incubated on ice with saturating concentrations of the following antibodies: Fig. 1, anti-CD8–FITC, anti-TCR–PE (PharMingen, San Diego, CA), and anti-CD4–Red613 (GIBCO BRL, Gaithersburg, MD); Figs. 2 and 4, anti-TCR–FITC (H57-597), anti-CD4–PE (Boehringer-Mannheim, Mannheim, Federal Republic of Germany), and anti-CD8–Red613 (GIBCO BRL, Gaithersburg, MD). The samples were analyzed on a FACScan® using LYSYS II software (Becton Dickinson, Mountain View, CA).


Quantitative impact of thymic clonal deletion on the T cell repertoire.

van Meerwijk JP, Marguerat S, Lees RK, Germain RN, Fowlkes BJ, MacDonald HR - J. Exp. Med. (1997)

Accelerated kinetics of generation of CD4SP and CD8SP  thymocytes in wild-type hosts lacking MHC class II or I, respectively, on  hematopoietic elements. 6-wk-old wt→ wt (n = 3, day 9; n = 6, days 10– 13), MHC I°II°→ wt (n = 3 each day), and MHC I°→ wt (n = 3) chimeras were sublethally irradiated (720 rads) and analyzed on day 9–13 as in  Fig. 2. Data represent average percentage of CD4+CD8−TCRhigh and  CD4−CD8+TCRhigh thymocytes ± SD.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196036&req=5

Figure 4: Accelerated kinetics of generation of CD4SP and CD8SP thymocytes in wild-type hosts lacking MHC class II or I, respectively, on hematopoietic elements. 6-wk-old wt→ wt (n = 3, day 9; n = 6, days 10– 13), MHC I°II°→ wt (n = 3 each day), and MHC I°→ wt (n = 3) chimeras were sublethally irradiated (720 rads) and analyzed on day 9–13 as in Fig. 2. Data represent average percentage of CD4+CD8−TCRhigh and CD4−CD8+TCRhigh thymocytes ± SD.
Mentions: Single-cell suspensions of thymocytes were incubated on ice with saturating concentrations of the following antibodies: Fig. 1, anti-CD8–FITC, anti-TCR–PE (PharMingen, San Diego, CA), and anti-CD4–Red613 (GIBCO BRL, Gaithersburg, MD); Figs. 2 and 4, anti-TCR–FITC (H57-597), anti-CD4–PE (Boehringer-Mannheim, Mannheim, Federal Republic of Germany), and anti-CD8–Red613 (GIBCO BRL, Gaithersburg, MD). The samples were analyzed on a FACScan® using LYSYS II software (Becton Dickinson, Mountain View, CA).

Bottom Line: Interactions between major histocompatibility complex (MHC) molecules expressed on stromal cells and antigen-specific receptors on T cells shape the repertoire of mature T lymphocytes emerging from the thymus.The quantitative impact of negative selection on the potentially available repertoire is currently unknown.To address this issue, we have constructed radiation bone marrow chimeras in which MHC molecules are present on radioresistant thymic epithelial cells (to allow positive selection) but absent from radiosensitive hematopoietic elements responsible for negative selection.

View Article: PubMed Central - PubMed

Affiliation: Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.

ABSTRACT
Interactions between major histocompatibility complex (MHC) molecules expressed on stromal cells and antigen-specific receptors on T cells shape the repertoire of mature T lymphocytes emerging from the thymus. Some thymocytes with appropriate receptors are stimulated to undergo differentiation to the fully mature state (positive selection), whereas others with strongly autoreactive receptors are triggered to undergo programmed cell death before completing this differentiation process (negative selection). The quantitative impact of negative selection on the potentially available repertoire is currently unknown. To address this issue, we have constructed radiation bone marrow chimeras in which MHC molecules are present on radioresistant thymic epithelial cells (to allow positive selection) but absent from radiosensitive hematopoietic elements responsible for negative selection. In such chimeras, the number of mature thymocytes was increased by twofold as compared with appropriate control chimeras This increase in steady-state numbers of mature thymocytes was not related to proliferation, increased retention, or recirculation and was accompanied by a similar two- to threefold increase in the de novo rate of generation of mature cells. Taken together, our data indicate that half to two-thirds of the thymocytes able to undergo positive selection die before full maturation due to negative selection.

Show MeSH
Related in: MedlinePlus