Killing of myeloid APCs via HLA class I, CD2 and CD226 defines a novel mechanism of suppression by human Tr1 cells.
Bottom Line: Here, we defined that Tr1 cells specifically lyse myeloid APC through a granzyme B (GZB)- and perforin (PRF)-dependent mechanism that requires HLA class I recognition, CD54/lymphocyte function-associated antigen (LFA)-1 adhesion, and activation via killer cell Ig-like receptors (KIRs) and CD2.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.
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
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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.
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.