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Maximal proliferation of cytotoxic T lymphocytes requires reverse signaling through Fas ligand.

Suzuki I, Fink PJ - J. Exp. Med. (1998)

Bottom Line: To test this hypothesis directly, soluble FasIgG, a fusion protein of murine Fas and human IgG1, was added to FasL+ CTLs to demonstrate that blocking cell surface Fas-FasL interactions mimics the depression observed for FasL- CTLs.In contrast to these results with CD8+ T cells, alloantigen-stimulated FasL- CD4+ T cells proliferate vigorously compared to FasL+ cells.These data demonstrate that reverse signaling through FasL is required for CTLs to achieve maximal proliferation and may provide clues to differences in the homeostatic regulation of activated CD4+ and CD8+ T cells during an immune response.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, University of Washington, Seattle, Washington 98195, USA.

ABSTRACT
Fas ligand (FasL/CD95L) is best known for its role in delivering apoptotic signals through its receptor, Fas (APO-1/CD95). In this study, we present evidence that FasL has a second role as a signaling receptor. Alloantigen-specific proliferation by multiple FasL- murine CTL lines is depressed compared to that of FasL+ CTL lines. FasL- CTLs kill efficiently on a per recovered cell basis and can achieve wild-type levels of proliferation upon stimulation by optimal doses of anti-CD3, suggesting the lack of a costimulatory signal during antigen stimulation. To test this hypothesis directly, soluble FasIgG, a fusion protein of murine Fas and human IgG1, was added to FasL+ CTLs to demonstrate that blocking cell surface Fas-FasL interactions mimics the depression observed for FasL- CTLs. In addition, plate-bound FasIgG in conjunction with suboptimal anti-CD3 stimulation augments proliferative signals in FasL+ but not FasL- CTLs. In contrast to these results with CD8+ T cells, alloantigen-stimulated FasL- CD4+ T cells proliferate vigorously compared to FasL+ cells. These data demonstrate that reverse signaling through FasL is required for CTLs to achieve maximal proliferation and may provide clues to differences in the homeostatic regulation of activated CD4+ and CD8+ T cells during an immune response.

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Increased proliferation and cell recovery of primary FasL−  CD4+ T cells relative to FasL+ CD4+ T cells over the course of an MLC.  Purified CD4+ T cells from B6 and B6.gld mice were cultured (in the absence of rIL-2) with H-2bm12 splenocytes, and [3H]TdR uptake and viable  cell counts were measured over days 1–5 of culture. All data are presented  as in Fig. 1.
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Figure 2: Increased proliferation and cell recovery of primary FasL− CD4+ T cells relative to FasL+ CD4+ T cells over the course of an MLC. Purified CD4+ T cells from B6 and B6.gld mice were cultured (in the absence of rIL-2) with H-2bm12 splenocytes, and [3H]TdR uptake and viable cell counts were measured over days 1–5 of culture. All data are presented as in Fig. 1.

Mentions: In contrast to their CD8+ counterparts, CD4+ T cells lacking functional FasL proliferate vigorously upon alloantigenic stimulation. Purified CD4+ cells from B6.gld mice cultured with class II different B6.bm12 stimulators proliferated better (Fig. 2 a) and generated more cells over the course of the 5 d of MLC (Fig. 2 b) than did CD4+ cells from wild-type B6 mice. This observation demonstrates the differential requirement for functional FasL expression in the promotion of maximal proliferation by CD8+ but not CD4+ T cells.


Maximal proliferation of cytotoxic T lymphocytes requires reverse signaling through Fas ligand.

Suzuki I, Fink PJ - J. Exp. Med. (1998)

Increased proliferation and cell recovery of primary FasL−  CD4+ T cells relative to FasL+ CD4+ T cells over the course of an MLC.  Purified CD4+ T cells from B6 and B6.gld mice were cultured (in the absence of rIL-2) with H-2bm12 splenocytes, and [3H]TdR uptake and viable  cell counts were measured over days 1–5 of culture. All data are presented  as in Fig. 1.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199194&req=5

Figure 2: Increased proliferation and cell recovery of primary FasL− CD4+ T cells relative to FasL+ CD4+ T cells over the course of an MLC. Purified CD4+ T cells from B6 and B6.gld mice were cultured (in the absence of rIL-2) with H-2bm12 splenocytes, and [3H]TdR uptake and viable cell counts were measured over days 1–5 of culture. All data are presented as in Fig. 1.
Mentions: In contrast to their CD8+ counterparts, CD4+ T cells lacking functional FasL proliferate vigorously upon alloantigenic stimulation. Purified CD4+ cells from B6.gld mice cultured with class II different B6.bm12 stimulators proliferated better (Fig. 2 a) and generated more cells over the course of the 5 d of MLC (Fig. 2 b) than did CD4+ cells from wild-type B6 mice. This observation demonstrates the differential requirement for functional FasL expression in the promotion of maximal proliferation by CD8+ but not CD4+ T cells.

Bottom Line: To test this hypothesis directly, soluble FasIgG, a fusion protein of murine Fas and human IgG1, was added to FasL+ CTLs to demonstrate that blocking cell surface Fas-FasL interactions mimics the depression observed for FasL- CTLs.In contrast to these results with CD8+ T cells, alloantigen-stimulated FasL- CD4+ T cells proliferate vigorously compared to FasL+ cells.These data demonstrate that reverse signaling through FasL is required for CTLs to achieve maximal proliferation and may provide clues to differences in the homeostatic regulation of activated CD4+ and CD8+ T cells during an immune response.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, University of Washington, Seattle, Washington 98195, USA.

ABSTRACT
Fas ligand (FasL/CD95L) is best known for its role in delivering apoptotic signals through its receptor, Fas (APO-1/CD95). In this study, we present evidence that FasL has a second role as a signaling receptor. Alloantigen-specific proliferation by multiple FasL- murine CTL lines is depressed compared to that of FasL+ CTL lines. FasL- CTLs kill efficiently on a per recovered cell basis and can achieve wild-type levels of proliferation upon stimulation by optimal doses of anti-CD3, suggesting the lack of a costimulatory signal during antigen stimulation. To test this hypothesis directly, soluble FasIgG, a fusion protein of murine Fas and human IgG1, was added to FasL+ CTLs to demonstrate that blocking cell surface Fas-FasL interactions mimics the depression observed for FasL- CTLs. In addition, plate-bound FasIgG in conjunction with suboptimal anti-CD3 stimulation augments proliferative signals in FasL+ but not FasL- CTLs. In contrast to these results with CD8+ T cells, alloantigen-stimulated FasL- CD4+ T cells proliferate vigorously compared to FasL+ cells. These data demonstrate that reverse signaling through FasL is required for CTLs to achieve maximal proliferation and may provide clues to differences in the homeostatic regulation of activated CD4+ and CD8+ T cells during an immune response.

Show MeSH
Related in: MedlinePlus