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Mutation in fas ligand impairs maturation of thymocytes bearing moderate affinity T cell receptors.

Boursalian TE, Fink PJ - J. Exp. Med. (2003)

Bottom Line: Fas ligand, best known as a death-inducer, is also a costimulatory molecule required for maximal proliferation of mature antigen-specific CD4+ and CD8+ T cells.Mutant Fas ligand inhibits neither negative selection nor death by neglect.Fas ligand is therefore an inducer of death, a costimulator of peripheral T cell activation, and an accessory molecule in positive selection.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Box 357650, University of Washington, Seattle, WA 98195-7650, USA.

ABSTRACT
Fas ligand, best known as a death-inducer, is also a costimulatory molecule required for maximal proliferation of mature antigen-specific CD4+ and CD8+ T cells. We now extend the role of Fas ligand by showing that it can also influence thymocyte development. T cell maturation in some, but not all, strains of TCR transgenic mice is severely impaired in thymocytes expressing mutant Fas ligand incapable of interacting with Fas. Mutant Fas ligand inhibits neither negative selection nor death by neglect. Instead, it appears to modulate positive selection of thymocytes expressing both class I- and class II-restricted T cell receptors of moderate affinity for their positively selecting ligands. Fas ligand is therefore an inducer of death, a costimulator of peripheral T cell activation, and an accessory molecule in positive selection.

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The defect in OT-1.gld thymocyte maturation is T cell autonomous and cannot be rescued by neighboring wild-type thymocytes. (A) Single BM chimeras were analyzed 4, 6, and 8 wk after reconstitution; only the latter two time points are shown. Thymocytes were stained for CD4 and CD8 and mean percentages of donor CD8 SP cells were calculated for each chimera type (striped bars = OT-1 → B6; black bars = OT-1 → B6.gld; open bars = OT-1.gld → B6; gray bars = OT-1.gld → B6.gld). Error bars represent the range of two data points for each group. (B) Mixed BM chimeras were analyzed at 4, 6, and 8 wk after reconstitution; results from week 8 are shown. Top panels: CD4/CD8 profiles of thymocytes from the two different donor types (OT-1 or OT-1.gld) within a single B6 host. Bottom panels: CD4/CD8 profiles of thymocytes from the two different donor types (OT-1 or OT-1.gld) within a single B6.gld host. Dot plots are gated on donor type using Ly5 allelic differences to distinguish donors from each other and the host. Percentages of CD8 SP thymocytes contained within each donor component are shown. Data are representative of three experiments; n = 2–4 for each group.
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fig3: The defect in OT-1.gld thymocyte maturation is T cell autonomous and cannot be rescued by neighboring wild-type thymocytes. (A) Single BM chimeras were analyzed 4, 6, and 8 wk after reconstitution; only the latter two time points are shown. Thymocytes were stained for CD4 and CD8 and mean percentages of donor CD8 SP cells were calculated for each chimera type (striped bars = OT-1 → B6; black bars = OT-1 → B6.gld; open bars = OT-1.gld → B6; gray bars = OT-1.gld → B6.gld). Error bars represent the range of two data points for each group. (B) Mixed BM chimeras were analyzed at 4, 6, and 8 wk after reconstitution; results from week 8 are shown. Top panels: CD4/CD8 profiles of thymocytes from the two different donor types (OT-1 or OT-1.gld) within a single B6 host. Bottom panels: CD4/CD8 profiles of thymocytes from the two different donor types (OT-1 or OT-1.gld) within a single B6.gld host. Dot plots are gated on donor type using Ly5 allelic differences to distinguish donors from each other and the host. Percentages of CD8 SP thymocytes contained within each donor component are shown. Data are representative of three experiments; n = 2–4 for each group.

Mentions: To localize the influence of FasL on T cell maturation to either the thymic epithelium or BM-derived cells, radiation chimeras were constructed using OT-1 or OT-1.gld BM donors and irradiated B6 or B6.gld hosts. In each of the four types of chimeras analyzed at all time points, the thymocyte subcompartment composition was dependent upon the BM donor type. Representation of donor CD8 SP thymocytes was diminished using OT-1.gld BM, whether the host was of wild-type (Fig. 3 A, open bars) or gld background (gray bars), compared with that of wild-type OT-1 BM in either host (striped and black bars). Therefore, FasL expression by BM-derived cells dictates the pattern of thymocyte maturation, while FasL expression by radioresistant thymic epithelial cells does not.


Mutation in fas ligand impairs maturation of thymocytes bearing moderate affinity T cell receptors.

Boursalian TE, Fink PJ - J. Exp. Med. (2003)

The defect in OT-1.gld thymocyte maturation is T cell autonomous and cannot be rescued by neighboring wild-type thymocytes. (A) Single BM chimeras were analyzed 4, 6, and 8 wk after reconstitution; only the latter two time points are shown. Thymocytes were stained for CD4 and CD8 and mean percentages of donor CD8 SP cells were calculated for each chimera type (striped bars = OT-1 → B6; black bars = OT-1 → B6.gld; open bars = OT-1.gld → B6; gray bars = OT-1.gld → B6.gld). Error bars represent the range of two data points for each group. (B) Mixed BM chimeras were analyzed at 4, 6, and 8 wk after reconstitution; results from week 8 are shown. Top panels: CD4/CD8 profiles of thymocytes from the two different donor types (OT-1 or OT-1.gld) within a single B6 host. Bottom panels: CD4/CD8 profiles of thymocytes from the two different donor types (OT-1 or OT-1.gld) within a single B6.gld host. Dot plots are gated on donor type using Ly5 allelic differences to distinguish donors from each other and the host. Percentages of CD8 SP thymocytes contained within each donor component are shown. Data are representative of three experiments; n = 2–4 for each group.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2194074&req=5

fig3: The defect in OT-1.gld thymocyte maturation is T cell autonomous and cannot be rescued by neighboring wild-type thymocytes. (A) Single BM chimeras were analyzed 4, 6, and 8 wk after reconstitution; only the latter two time points are shown. Thymocytes were stained for CD4 and CD8 and mean percentages of donor CD8 SP cells were calculated for each chimera type (striped bars = OT-1 → B6; black bars = OT-1 → B6.gld; open bars = OT-1.gld → B6; gray bars = OT-1.gld → B6.gld). Error bars represent the range of two data points for each group. (B) Mixed BM chimeras were analyzed at 4, 6, and 8 wk after reconstitution; results from week 8 are shown. Top panels: CD4/CD8 profiles of thymocytes from the two different donor types (OT-1 or OT-1.gld) within a single B6 host. Bottom panels: CD4/CD8 profiles of thymocytes from the two different donor types (OT-1 or OT-1.gld) within a single B6.gld host. Dot plots are gated on donor type using Ly5 allelic differences to distinguish donors from each other and the host. Percentages of CD8 SP thymocytes contained within each donor component are shown. Data are representative of three experiments; n = 2–4 for each group.
Mentions: To localize the influence of FasL on T cell maturation to either the thymic epithelium or BM-derived cells, radiation chimeras were constructed using OT-1 or OT-1.gld BM donors and irradiated B6 or B6.gld hosts. In each of the four types of chimeras analyzed at all time points, the thymocyte subcompartment composition was dependent upon the BM donor type. Representation of donor CD8 SP thymocytes was diminished using OT-1.gld BM, whether the host was of wild-type (Fig. 3 A, open bars) or gld background (gray bars), compared with that of wild-type OT-1 BM in either host (striped and black bars). Therefore, FasL expression by BM-derived cells dictates the pattern of thymocyte maturation, while FasL expression by radioresistant thymic epithelial cells does not.

Bottom Line: Fas ligand, best known as a death-inducer, is also a costimulatory molecule required for maximal proliferation of mature antigen-specific CD4+ and CD8+ T cells.Mutant Fas ligand inhibits neither negative selection nor death by neglect.Fas ligand is therefore an inducer of death, a costimulator of peripheral T cell activation, and an accessory molecule in positive selection.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Box 357650, University of Washington, Seattle, WA 98195-7650, USA.

ABSTRACT
Fas ligand, best known as a death-inducer, is also a costimulatory molecule required for maximal proliferation of mature antigen-specific CD4+ and CD8+ T cells. We now extend the role of Fas ligand by showing that it can also influence thymocyte development. T cell maturation in some, but not all, strains of TCR transgenic mice is severely impaired in thymocytes expressing mutant Fas ligand incapable of interacting with Fas. Mutant Fas ligand inhibits neither negative selection nor death by neglect. Instead, it appears to modulate positive selection of thymocytes expressing both class I- and class II-restricted T cell receptors of moderate affinity for their positively selecting ligands. Fas ligand is therefore an inducer of death, a costimulator of peripheral T cell activation, and an accessory molecule in positive selection.

Show MeSH
Related in: MedlinePlus