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: Tr1 polarized cell lines expressed significantly higher levels of GZB compared to Th0-cell lines (97.3 versus 12.9%, n=11, p<0.0001, Fig. 1A). Notably, IL-10-producing Tr1 cells represent 10–15% of the polarized population, thus GZB expression is not restricted to this population of cells (Fig. 1B). Tr1-cell lines express also significantly higher levels of GZA compared to Th0-cell lines (58.7% versus 9%, n=8, p<0.0001, not shown), nevertheless its expression was consistently lower than that of GZB. Tr1-cell lines contained a significantly higher percentage of PRF+ cells compared to Th0-cell lines before (8.8 versus 1.8%, n=7, p=0.015) and after stimulation (13.3 versus 5.1%, n=7, p=0.007, not shown).
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.