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Killing of myeloid APCs via HLA class I, CD2 and CD226 defines a novel mechanism of suppression by human Tr1 cells.

Magnani CF, Alberigo G, Bacchetta R, Serafini G, Andreani M, Roncarolo MG, Gregori S - Eur. J. Immunol. (2011)

Bottom Line: Notably, interaction between CD226 on Tr1 cells and their ligands on myeloid cells, leading to Tr1-cell activation, is necessary for defining Tr1-cell target specificity.We also showed that high frequency of GZB-expressing CD4(+) T cells is detected in tolerant patients and correlates with elevated occurrence of IL-10-producing CD4(+) T cells.In conclusion, the modulatory activities of Tr1 cells are not only due to suppressive cytokines but also to specific cell-to-cell interactions that lead to selective killing of myeloid cells and possibly bystander suppression.

View Article: PubMed Central - PubMed

Affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.

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Tr1-mediated cytotoxicity is HLA class I-dependent. (A) Tr1-cell lines were co-cultured with U937 target cell line at 100:1 (E:T) ratio in the presence of anti-HLA class I mAb or IgG2a,k isotype control at the indicated concentrations, and cytotoxicity was determined by 51Cr release. Mean±SE of four donors performed in two independent experiments are reported. (B) Tr1-cell lines were co-cultured with freshly isolated autologous CD14+ and CD1c+ cells at 10:1 (E:T) ratio in the presence of anti-HLA-I mAb or IgG2a,k isotype control, and degranulation in the presence of GZB was measured by co-expression of CD107a and GZB in CD4+ T cells. One donor representative of three donors performed in a single experiment is shown. Numbers represent percentage of CD107a+GZB+ cells. (C) Tr1-cell clones were co-cultured with U937 target cell at 10:1 (E:T) ratio in the presence of anti-HLA-I mAb or IgG2a,k isotype control, and degranulation was measured by co-expression of CD107a and GZB in CD4+ T cells. Numbers represent percentage of CD107a+GZB+ cells.
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fig05: Tr1-mediated cytotoxicity is HLA class I-dependent. (A) Tr1-cell lines were co-cultured with U937 target cell line at 100:1 (E:T) ratio in the presence of anti-HLA class I mAb or IgG2a,k isotype control at the indicated concentrations, and cytotoxicity was determined by 51Cr release. Mean±SE of four donors performed in two independent experiments are reported. (B) Tr1-cell lines were co-cultured with freshly isolated autologous CD14+ and CD1c+ cells at 10:1 (E:T) ratio in the presence of anti-HLA-I mAb or IgG2a,k isotype control, and degranulation in the presence of GZB was measured by co-expression of CD107a and GZB in CD4+ T cells. One donor representative of three donors performed in a single experiment is shown. Numbers represent percentage of CD107a+GZB+ cells. (C) Tr1-cell clones were co-cultured with U937 target cell at 10:1 (E:T) ratio in the presence of anti-HLA-I mAb or IgG2a,k isotype control, and degranulation was measured by co-expression of CD107a and GZB in CD4+ T cells. Numbers represent percentage of CD107a+GZB+ cells.

Mentions: Addition of a pan anti-HLA-I mAb (clone W6/32) significantly inhibited, in a dose-dependent manner, the killing of U937, CD14+, and CD1c+ cells (autologous and allogeneic) by Tr1-cell lines and by three distinct Tr1-cell clones (Fig. 5A–C and data not shown). Tr1 cells express a variety of activating killer cell Ig-like receptors (KIRs) including KIR2DS2, KIR2DS3, KIR3DS1, and KIR2DL4, the ligand specific for HLA-G (Table 2). Addition of neutralizing anti-HLA-G mAb (clone 87G) partially inhibited, in a dose-dependent manner, the killing of U937, CD14+, and CD1c+ cells by both Tr1-cell lines (Supporting Information Fig. 5A and B) and Tr1-cell clones (Supporting Information Fig. 5C), supporting the contribution of stimulatory KIRs in promoting the killing of target cells.


Killing of myeloid APCs via HLA class I, CD2 and CD226 defines a novel mechanism of suppression by human Tr1 cells.

Magnani CF, Alberigo G, Bacchetta R, Serafini G, Andreani M, Roncarolo MG, Gregori S - Eur. J. Immunol. (2011)

Tr1-mediated cytotoxicity is HLA class I-dependent. (A) Tr1-cell lines were co-cultured with U937 target cell line at 100:1 (E:T) ratio in the presence of anti-HLA class I mAb or IgG2a,k isotype control at the indicated concentrations, and cytotoxicity was determined by 51Cr release. Mean±SE of four donors performed in two independent experiments are reported. (B) Tr1-cell lines were co-cultured with freshly isolated autologous CD14+ and CD1c+ cells at 10:1 (E:T) ratio in the presence of anti-HLA-I mAb or IgG2a,k isotype control, and degranulation in the presence of GZB was measured by co-expression of CD107a and GZB in CD4+ T cells. One donor representative of three donors performed in a single experiment is shown. Numbers represent percentage of CD107a+GZB+ cells. (C) Tr1-cell clones were co-cultured with U937 target cell at 10:1 (E:T) ratio in the presence of anti-HLA-I mAb or IgG2a,k isotype control, and degranulation was measured by co-expression of CD107a and GZB in CD4+ T cells. Numbers represent percentage of CD107a+GZB+ cells.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3116154&req=5

fig05: Tr1-mediated cytotoxicity is HLA class I-dependent. (A) Tr1-cell lines were co-cultured with U937 target cell line at 100:1 (E:T) ratio in the presence of anti-HLA class I mAb or IgG2a,k isotype control at the indicated concentrations, and cytotoxicity was determined by 51Cr release. Mean±SE of four donors performed in two independent experiments are reported. (B) Tr1-cell lines were co-cultured with freshly isolated autologous CD14+ and CD1c+ cells at 10:1 (E:T) ratio in the presence of anti-HLA-I mAb or IgG2a,k isotype control, and degranulation in the presence of GZB was measured by co-expression of CD107a and GZB in CD4+ T cells. One donor representative of three donors performed in a single experiment is shown. Numbers represent percentage of CD107a+GZB+ cells. (C) Tr1-cell clones were co-cultured with U937 target cell at 10:1 (E:T) ratio in the presence of anti-HLA-I mAb or IgG2a,k isotype control, and degranulation was measured by co-expression of CD107a and GZB in CD4+ T cells. Numbers represent percentage of CD107a+GZB+ cells.
Mentions: Addition of a pan anti-HLA-I mAb (clone W6/32) significantly inhibited, in a dose-dependent manner, the killing of U937, CD14+, and CD1c+ cells (autologous and allogeneic) by Tr1-cell lines and by three distinct Tr1-cell clones (Fig. 5A–C and data not shown). Tr1 cells express a variety of activating killer cell Ig-like receptors (KIRs) including KIR2DS2, KIR2DS3, KIR3DS1, and KIR2DL4, the ligand specific for HLA-G (Table 2). Addition of neutralizing anti-HLA-G mAb (clone 87G) partially inhibited, in a dose-dependent manner, the killing of U937, CD14+, and CD1c+ cells by both Tr1-cell lines (Supporting Information Fig. 5A and B) and Tr1-cell clones (Supporting Information Fig. 5C), supporting the contribution of stimulatory KIRs in promoting the killing of target cells.

Bottom Line: Notably, interaction between CD226 on Tr1 cells and their ligands on myeloid cells, leading to Tr1-cell activation, is necessary for defining Tr1-cell target specificity.We also showed that high frequency of GZB-expressing CD4(+) T cells is detected in tolerant patients and correlates with elevated occurrence of IL-10-producing CD4(+) T cells.In conclusion, the modulatory activities of Tr1 cells are not only due to suppressive cytokines but also to specific cell-to-cell interactions that lead to selective killing of myeloid cells and possibly bystander suppression.

View Article: PubMed Central - PubMed

Affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.

Show MeSH
Related in: MedlinePlus