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The Src family tyrosine kinase Fyn regulates natural killer T cell development.

Gadue P, Morton N, Stein PL - J. Exp. Med. (1999)

Bottom Line: Here, it is shown that Fyn is required for the rapid burst of interleukin (IL)-4 and IL-13 synthesis, which occurs promptly after T cell receptor activation.Both NK T cells and conventional T cells express similar levels of Lck, implying that Fyn and Lck have distinct roles in regulating NK T cell ontogeny.The fyn mutation defines the first signaling molecule that is selectively required for NK T cell, but not for T lymphocyte or NK cell development.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Immunology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

ABSTRACT
T lymphocytes express two Src tyrosine kinases, Lck and Fyn. While thymocyte and T cell subsets are largely normal in fyn(-/-) mice, animals lacking Lck have impaired T cell development. Here, it is shown that Fyn is required for the rapid burst of interleukin (IL)-4 and IL-13 synthesis, which occurs promptly after T cell receptor activation. The lack of cytokine induction in fyn mutant mice is due to a block in natural killer (NK) T cell development. Studies using bone marrow chimeras indicate that the defect behaves in a cell-autonomous manner, and the lack of NK T cells is probably not caused by inappropriate microenvironmental cues. Both NK T cells and conventional T cells express similar levels of Lck, implying that Fyn and Lck have distinct roles in regulating NK T cell ontogeny. The fyn mutation defines the first signaling molecule that is selectively required for NK T cell, but not for T lymphocyte or NK cell development.

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The fyn mutation may function in a cell-autonomous manner during NK T cell development. Irradiated mice were injected with a mix of wild-type 129Sv (NK1.1−; Ly9.1+) and wild-type or mutant C57Bl/6 (NK1.1+; Ly9.1−) derived bone marrow. (A) Reconstitution of NK T cells in the thymus by the different bone marrows was assessed by flow cytometry as in Fig. 2. NK T cells developed from wild-type (Wt) and β2M mutant bone marrow, but not fyn mutant bone marrow. (B) The relative contribution of 129Sv- and C57Bl/6-derived lymphoid cells in the thymus was determined by comparing Ly9.1 expression on CD4+ thymocytes by flow cytometry. All the radiation chimeras contain a mix of CD4+ thymocytes derived from the two strains. The data presented are representative of two independent experiments (chimeras: wild-type, n = 7; Fyn, n = 7; β2M, n = 4).
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Figure 3: The fyn mutation may function in a cell-autonomous manner during NK T cell development. Irradiated mice were injected with a mix of wild-type 129Sv (NK1.1−; Ly9.1+) and wild-type or mutant C57Bl/6 (NK1.1+; Ly9.1−) derived bone marrow. (A) Reconstitution of NK T cells in the thymus by the different bone marrows was assessed by flow cytometry as in Fig. 2. NK T cells developed from wild-type (Wt) and β2M mutant bone marrow, but not fyn mutant bone marrow. (B) The relative contribution of 129Sv- and C57Bl/6-derived lymphoid cells in the thymus was determined by comparing Ly9.1 expression on CD4+ thymocytes by flow cytometry. All the radiation chimeras contain a mix of CD4+ thymocytes derived from the two strains. The data presented are representative of two independent experiments (chimeras: wild-type, n = 7; Fyn, n = 7; β2M, n = 4).

Mentions: Thymocytes from each group were analyzed for the presence of NK T cells by flow cytometry. Irradiated mice which received either wild-type or β2M mutant bone marrow developed NK T cells (Fig. 3 A). Since β2M is required for stable surface expression of CD1, this result indicated that the CD1d present on wild-type 129Sv cells was able to complement the defect and allow the β2M-deficient lymphocytes to undergo selection and form NK T cells. In contrast, mice receiving the mixture of 129Sv and fyn mutant bone marrow had no detectable NK T cells. Because the wild-type 129Sv–derived cells were unable to rescue NK T cell development in the fyn mutant chimera, it is likely that this is a cell-autonomous defect in the NK T cell or progenitor. Fig. 3 B shows that all of the chimeras contain C57Bl/6-derived thymocytes at similar levels. Chimerism extended to the periphery, since spleens from all reconstituted mice contained C57Bl/6-derived NK cells and T lymphocytes as well (data not shown). This indicates that the lack of NK T cells in the chimeras made from fyn mutants is not due to poor colonization by fyn mutant bone marrow.


The Src family tyrosine kinase Fyn regulates natural killer T cell development.

Gadue P, Morton N, Stein PL - J. Exp. Med. (1999)

The fyn mutation may function in a cell-autonomous manner during NK T cell development. Irradiated mice were injected with a mix of wild-type 129Sv (NK1.1−; Ly9.1+) and wild-type or mutant C57Bl/6 (NK1.1+; Ly9.1−) derived bone marrow. (A) Reconstitution of NK T cells in the thymus by the different bone marrows was assessed by flow cytometry as in Fig. 2. NK T cells developed from wild-type (Wt) and β2M mutant bone marrow, but not fyn mutant bone marrow. (B) The relative contribution of 129Sv- and C57Bl/6-derived lymphoid cells in the thymus was determined by comparing Ly9.1 expression on CD4+ thymocytes by flow cytometry. All the radiation chimeras contain a mix of CD4+ thymocytes derived from the two strains. The data presented are representative of two independent experiments (chimeras: wild-type, n = 7; Fyn, n = 7; β2M, n = 4).
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Related In: Results  -  Collection

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Figure 3: The fyn mutation may function in a cell-autonomous manner during NK T cell development. Irradiated mice were injected with a mix of wild-type 129Sv (NK1.1−; Ly9.1+) and wild-type or mutant C57Bl/6 (NK1.1+; Ly9.1−) derived bone marrow. (A) Reconstitution of NK T cells in the thymus by the different bone marrows was assessed by flow cytometry as in Fig. 2. NK T cells developed from wild-type (Wt) and β2M mutant bone marrow, but not fyn mutant bone marrow. (B) The relative contribution of 129Sv- and C57Bl/6-derived lymphoid cells in the thymus was determined by comparing Ly9.1 expression on CD4+ thymocytes by flow cytometry. All the radiation chimeras contain a mix of CD4+ thymocytes derived from the two strains. The data presented are representative of two independent experiments (chimeras: wild-type, n = 7; Fyn, n = 7; β2M, n = 4).
Mentions: Thymocytes from each group were analyzed for the presence of NK T cells by flow cytometry. Irradiated mice which received either wild-type or β2M mutant bone marrow developed NK T cells (Fig. 3 A). Since β2M is required for stable surface expression of CD1, this result indicated that the CD1d present on wild-type 129Sv cells was able to complement the defect and allow the β2M-deficient lymphocytes to undergo selection and form NK T cells. In contrast, mice receiving the mixture of 129Sv and fyn mutant bone marrow had no detectable NK T cells. Because the wild-type 129Sv–derived cells were unable to rescue NK T cell development in the fyn mutant chimera, it is likely that this is a cell-autonomous defect in the NK T cell or progenitor. Fig. 3 B shows that all of the chimeras contain C57Bl/6-derived thymocytes at similar levels. Chimerism extended to the periphery, since spleens from all reconstituted mice contained C57Bl/6-derived NK cells and T lymphocytes as well (data not shown). This indicates that the lack of NK T cells in the chimeras made from fyn mutants is not due to poor colonization by fyn mutant bone marrow.

Bottom Line: Here, it is shown that Fyn is required for the rapid burst of interleukin (IL)-4 and IL-13 synthesis, which occurs promptly after T cell receptor activation.Both NK T cells and conventional T cells express similar levels of Lck, implying that Fyn and Lck have distinct roles in regulating NK T cell ontogeny.The fyn mutation defines the first signaling molecule that is selectively required for NK T cell, but not for T lymphocyte or NK cell development.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Immunology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

ABSTRACT
T lymphocytes express two Src tyrosine kinases, Lck and Fyn. While thymocyte and T cell subsets are largely normal in fyn(-/-) mice, animals lacking Lck have impaired T cell development. Here, it is shown that Fyn is required for the rapid burst of interleukin (IL)-4 and IL-13 synthesis, which occurs promptly after T cell receptor activation. The lack of cytokine induction in fyn mutant mice is due to a block in natural killer (NK) T cell development. Studies using bone marrow chimeras indicate that the defect behaves in a cell-autonomous manner, and the lack of NK T cells is probably not caused by inappropriate microenvironmental cues. Both NK T cells and conventional T cells express similar levels of Lck, implying that Fyn and Lck have distinct roles in regulating NK T cell ontogeny. The fyn mutation defines the first signaling molecule that is selectively required for NK T cell, but not for T lymphocyte or NK cell development.

Show MeSH
Related in: MedlinePlus