FAS/FAS-L dependent killing of activated human monocytes and macrophages by CD4+CD25-responder T cells, but not CD4+CD25+regulatory T cells

TY - JOUR

T1 - FAS/FAS-L dependent killing of activated human monocytes and macrophages by CD4+CD25-responder T cells, but not CD4+CD25+regulatory T cells

AU - Jagger, Ann L

AU - Evans, Hayley G

AU - Walter, Gina J

AU - Gullick, Nicola J

AU - Menon, Bina

AU - Ballantine, Lucy E

AU - Gracie, Alastair

AU - Magerus-Chatinet, Aude

AU - Tiemessen, Machteld M

AU - Geissmann, Frederic

AU - Rieux-Laucat, Frederic

AU - Taams, Leonie S

N1 - Copyright © 2011 Elsevier Ltd. All rights reserved.

PY - 2012/2

Y1 - 2012/2

N2 - Conclusive resolution of an immune response is critical for the prevention of autoimmunity and chronic inflammation. We report that following co-culture with autologous CD4+CD25- responder T cells, human CD14+ monocytes and monocyte-derived macrophages become activated but also significantly more prone to apoptosis than monocytes/macrophages cultured alone. In contrast, in the presence of CD4+CD25+ regulatory T cells (Tregs), monocytes and macrophages survive whilst adopting an anti-inflammatory phenotype. The induction of monocyte death requires responder T cell activation and cell-contact between responder T cells and monocytes. We demonstrate a critical role for FAS/FAS-L ligation in responder T cell-induced monocyte killing since responder T cells, but not Tregs, upregulate FAS-ligand (FAS-L) mRNA, and induce FAS expression on monocytes. Furthermore, responder T cell-induced monocyte apoptosis is blocked by neutralising FAS/FAS-L interaction, and is not observed when monocytes from an autoimmune lymphoproliferative syndrome (ALPS) patient with complete FAS-deficiency are used as target cells. Finally, we show that responder T cell-induced killing of monocytes is impaired in patients with active rheumatoid arthritis (RA). Our data suggest that resolution of inflammation in the course of a healthy immune response is aided by the unperturbed killing of monocytes with inflammatory potential by responder T cells and the induction of longer-lived, Treg-induced, anti-inflammatory monocytes. (C) 2011 Elsevier Ltd. All rights reserved.

AB - Conclusive resolution of an immune response is critical for the prevention of autoimmunity and chronic inflammation. We report that following co-culture with autologous CD4+CD25- responder T cells, human CD14+ monocytes and monocyte-derived macrophages become activated but also significantly more prone to apoptosis than monocytes/macrophages cultured alone. In contrast, in the presence of CD4+CD25+ regulatory T cells (Tregs), monocytes and macrophages survive whilst adopting an anti-inflammatory phenotype. The induction of monocyte death requires responder T cell activation and cell-contact between responder T cells and monocytes. We demonstrate a critical role for FAS/FAS-L ligation in responder T cell-induced monocyte killing since responder T cells, but not Tregs, upregulate FAS-ligand (FAS-L) mRNA, and induce FAS expression on monocytes. Furthermore, responder T cell-induced monocyte apoptosis is blocked by neutralising FAS/FAS-L interaction, and is not observed when monocytes from an autoimmune lymphoproliferative syndrome (ALPS) patient with complete FAS-deficiency are used as target cells. Finally, we show that responder T cell-induced killing of monocytes is impaired in patients with active rheumatoid arthritis (RA). Our data suggest that resolution of inflammation in the course of a healthy immune response is aided by the unperturbed killing of monocytes with inflammatory potential by responder T cells and the induction of longer-lived, Treg-induced, anti-inflammatory monocytes. (C) 2011 Elsevier Ltd. All rights reserved.

U2 - 10.1016/j.jaut.2011.11.015

DO - 10.1016/j.jaut.2011.11.015

M3 - Article

C2 - 22197557

VL - 38

SP - 29

EP - 38

JO - Journal of Autoimmunity

JF - Journal of Autoimmunity

IS - 1

ER -