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: To dissect the molecular mechanism underlying the target specificity of Tr1 cells, we investigated adhesion and signaling molecules involved in Tr1-myeloid APC interaction. Both CD14+ and CD1c+ cells expressed higher levels of CD54 compared to T and B cells (not shown), and Tr1 cells expressed LFA-1 (CD18/CD11a), the CD54 ligand (Supporting Information Fig. 6). Addition of neutralizing anti-CD18 mAb blocked degranulation of Tr1-cell lines when co-cultured with CD14+ or CD1c+ cells (Fig. 6A). CD54 expression on target cells is specifically involved in the formation of a stable immunological synapse essential for cytotoxicity mediated by NK cells and CTLs 14. Therefore, our findings suggest that the high expression of CD54 on myeloid cells is responsible for the formation of a stable and prolong interaction with Tr1 cells, leading to lysis of the target cell.
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.