CCR8 + FOXp3 + T reg cells as master drivers of immune regulation.

Autor: Barsheshet Y; Department of Immunology, Technion, Haifa 31096, Israel., Wildbaum G; Department of Immunology, Technion, Haifa 31096, Israel., Levy E; Department of Immunology, Technion, Haifa 31096, Israel., Vitenshtein A; Department of Immunology, Technion, Haifa 31096, Israel., Akinseye C; GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire, SG1 2NY, United Kingdom., Griggs J; GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire, SG1 2NY, United Kingdom., Lira SA; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Karin N; Department of Immunology, Technion, Haifa 31096, Israel; nkarin10@gmail.com.; Rappaport Family Institute for Research in the Medical Sciences and Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Jun 06; Vol. 114 (23), pp. 6086-6091. Date of Electronic Publication: 2017 May 22.
DOI: 10.1073/pnas.1621280114
Abstrakt: The current study identifies CCR8 + regulatory T cells (T reg cells) as drivers of immunosuppression. We show that in human peripheral blood cells, more than 30% of T reg up-regulate CCR8 following activation in the presence of CCL1. This interaction induces STAT3-dependent up-regulation of FOXp3, CD39, IL-10, and granzyme B, resulting in enhanced suppressive activity of these cells. Of the four human CCR8 ligands, CCL1 is unique in potentiating T reg cells. The relevance of these observations has been extended using an experimental model of multiple sclerosis [experimental autoimmune encephalomyelitis, (EAE)] and a stabilized version of mouse CCL1 (CCL1-Ig). First, we identified a self-feeding mechanism by which CCL1 produced by T reg cells at an autoimmune site up-regulates the expression of its own receptor, CCR8, on these cells. Administration of CCL1-Ig during EAE enhanced the in vivo proliferation of these CCR8 + regulatory cells while inducing the expression of CD39, granzyme B, and IL-10, resulting in the efficacious suppression of ongoing EAE. The critical role of the CCL1-CCR8 axis in T reg cells was further dissected through adoptive transfer studies using CCR8 -/- mice. Collectively, we demonstrate the pivotal role of CCR8 + T reg cells in restraining immunity and highlight the potential clinical implications of this discovery.
Competing Interests: Conflict of interest statement: N.K., Y.B., and G.W. hold a pending patent on CCL1-based therapy of autoimmunity and graft-versus-host disease that has been outlicensed to GlaxoSmithKline.
Databáze: MEDLINE
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