By now it is clear that Tregs consist of many different T-cell su

By now it is clear that Tregs consist of many different T-cell subsets that can be distinguished by their development: Naturally occurring CD4+CD25+ Foxp3+ Tregs arise during the normal process of maturation in the thymus, whereas inducible Tregs are generated in the periphery during immune responses 6, 22, 23, 29. The generation of Tregs by specific modes of stimulation, especially in a particular cytokine milieu, has been described by several groups 10, 30. For instance, Tr1 cells arise from naive precursors and can be differentiated both in vitro and in vivo by repeated TCR stimulation in the presence of IL-10 10, 30. Our data demonstrate

that DN T cells belong to the inducible Treg subset that Trametinib concentration exerts their suppressive activity exclusively after activation with APCs. Similar to our observation, Zhang et al. reported that murine DN T cells suppress transplant rejection only after previous in vivo activation induced by donor lymphocyte infusion 11, 13, 17, 19. Of note, once the regulatory function of DN T cells has been induced, they retain their suppressive activity GDC-0980 chemical structure upon repetitive stimulation.

Although human DN T cells are only present at low numbers 12, they can be induced to Tregs and expanded ex vivo for clinical application. The mechanisms by which Tregs mediate suppression are highly diverse: Several studies demonstrated that murine DN T cells acquire peptide-MHC-complexes from APCs and interact via transferred molecules with effector T cells 11, 31, 32. We have previously demonstrated that human DN T cells were also able to acquire MHC-complexes 12. By now it is clear that various cell populations can acquire membrane fragments from APCs, a process called trogocytosis. However, DN T-cell-mediated suppression was not affected when plate-bound anti-CD3 mAb or artificial APCs were used as stimulators. In addition, blocking trogocytosis via CMA was not able to abrogate the suppressive activity of human DN T cells (our unpublished data), indicating

that human DN T cells suppress responder T cells by other mechanisms. Several studies demonstrated that murine DN T cells mediate suppression by eliminating Thiamine-diphosphate kinase T cells through Fas/FasL interaction or via perforin/granzyme 11, 13, 15, 16, 19, 20. Previously, we have shown that human DN T cells induce apoptosis in highly activated CD8+ T-cell lines 12. However, in the prior study, we used DN T cells as suppressors that acquired peptide-MHC-complexes from APCs. Tsang et al. demonstrated that T cells can induce apoptosis in neighboring T cells following acquisition of MHC-complexes 33. Thus, induction of apoptosis might be a process that is not specific for the suppressive activity of human DN T cells.

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