LAG3+ Regulatory T Cells Restrain Interleukin-23 Producing CX3CR1+ Gut-Resident Macrophages during Group 3 Innate Lymphoid Cell-Driven Colitis

被引:168
作者
Bauche, David [1 ]
Joyce-Shaikh, Barbara [1 ]
Jain, Renu [1 ]
Grein, Jeff [1 ]
Ku, Karin S. [1 ]
Blumenschein, Wendy M. [1 ]
Ganal-Vonarburg, Stephanie C. [2 ]
Wilson, Douglas C. [1 ]
McClanahan, Terrill K. [1 ]
Malefyt, Rene de Waal [1 ]
Macpherson, Andrew J. [2 ]
Annamalai, Lakshmanan [1 ]
Yearley, Jennifer H. [1 ]
Cua, Daniel J. [1 ]
机构
[1] Merck & Co Inc, MRL, Palo Alto, CA 94304 USA
[2] Univ Bern, Univ Klin Viszerale Chirurg & Med, Inselspital, Maurice Muller Labs DKF, Murtenstr 35, CH-3008 Bern, Switzerland
关键词
GENOME-WIDE ASSOCIATION; CLASS-II ENGAGEMENT; DENDRITIC CELLS; ORAL TOLERANCE; LAG-3; EXPRESSION; INFLAMMATION; HOMEOSTASIS; LIGAND; IL-22;
D O I
10.1016/j.immuni.2018.07.007
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Interleukin-22 (IL-22)-producing group 3 innate lymphoid cells (ILC3) maintains gut homeostasis but can also promote inflammatory bowel disease (IBD). The regulation of ILC3-dependent colitis remains to be elucidated. Here we show that Foxp3(+) regulatory T cells (Treg cells) prevented ILC3-mediated colitis in an IL-10-independent manner. Treg cells inhibited IL-23 and IL-1 beta production from intestinal-resident CX3CR1(+) macrophages but not CD103(+) dendritic cells. Moreover, Treg cells restrained ILC3 production of IL-22 through suppression of CX3CR1(+) macrophage production of IL-23 and IL-1b. This suppression was contact dependent and was mediated by latent activation gene-3 (LAG-3)-an immune checkpoint receptor-expressed on Treg cells. Engagement of LAG-3 on MHC class II drove profound immunosuppression of CX3CR1(+) tissue-resident macrophages. Our study reveals that the health of the intestinal mucosa is maintained by an axis driven by Treg cells communication with resident macrophages that withhold inflammatory stimuli required for ILC3 function.
引用
收藏
页码:342 / +
页数:16
相关论文
共 59 条
[1]   Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation [J].
Anderson, Ana C. ;
Joller, Nicole ;
Kuchroo, Vijay K. .
IMMUNITY, 2016, 44 (05) :989-1004
[2]   MHC class II signal transduction in human dendritic cells induced by a natural ligand, the LAG-3 protein (CD223) [J].
Andreae, S ;
Buisson, S ;
Triebel, F .
BLOOD, 2003, 102 (06) :2130-2137
[3]   LAG3 (CD223) as a cancer immunotherapy target [J].
Andrews, Lawrence P. ;
Marciscano, Ariel E. ;
Drake, Charles G. ;
Vignali, Dario A. A. .
IMMUNOLOGICAL REVIEWS, 2017, 276 (01) :80-96
[4]   Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage [J].
Aparicio-Domingo, Patricia ;
Romera-Hernandez, Monica ;
Karrich, Julien J. ;
Cornelissen, Ferry ;
Papazian, Natalie ;
Lindenbergh-Kortleve, Dicky J. ;
Butler, James A. ;
Boon, Louis ;
Coles, Mark C. ;
Samsom, Janneke N. ;
Cupedo, Tom .
JOURNAL OF EXPERIMENTAL MEDICINE, 2015, 212 (11) :1783-1791
[5]   IL-23-mediated mononuclear phagocyte crosstalk protects mice from Citrobacter rodentium-induced colon immunopathology [J].
Aychek, Tegest ;
Mildner, Alexander ;
Yona, Simon ;
Kim, Ki-Wook ;
Lampl, Nardy ;
Reich-Zeliger, Shlomit ;
Boon, Louis ;
Yogev, Nir ;
Waisman, Ari ;
Cua, Daniel J. ;
Jung, Steffen .
NATURE COMMUNICATIONS, 2015, 6
[6]   Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease [J].
Barrett, Jeffrey C. ;
Hansoul, Sarah ;
Nicolae, Dan L. ;
Cho, Judy H. ;
Duerr, Richard H. ;
Rioux, John D. ;
Brant, Steven R. ;
Silverberg, Mark S. ;
Taylor, Kent D. ;
Barmada, M. Michael ;
Bitton, Alain ;
Dassopoulos, Themistocles ;
Datta, Lisa Wu ;
Green, Todd ;
Griffiths, Anne M. ;
Kistner, Emily O. ;
Murtha, Michael T. ;
Regueiro, Miguel D. ;
Rotter, Jerome I. ;
Schumm, L. Philip ;
Steinhart, A. Hillary ;
Targan, Stephan R. ;
Xavier, Ramnik J. ;
Libioulle, Cecile ;
Sandor, Cynthia ;
Lathrop, Mark ;
Belaiche, Jacques ;
Dewit, Olivier ;
Gut, Ivo ;
Heath, Simon ;
Laukens, Debby ;
Mni, Myriam ;
Rutgeerts, Paul ;
Van Gossum, Andre ;
Zelenika, Diana ;
Franchimont, Denis ;
Hugot, Jean-Pierre ;
de Vos, Martine ;
Vermeire, Severine ;
Louis, Edouard ;
Cardon, Lon R. ;
Anderson, Carl A. ;
Drummond, Hazel ;
Nimmo, Elaine ;
Ahmad, Tariq ;
Prescott, Natalie J. ;
Onnie, Clive M. ;
Fisher, Sheila A. ;
Marchini, Jonathan ;
Ghori, Jilur .
NATURE GENETICS, 2008, 40 (08) :955-962
[7]   IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration [J].
Brand, S ;
Beigel, F ;
Olszak, T ;
Zitzmann, K ;
Eichhorst, ST ;
Otte, JM ;
Diepolder, H ;
Marquardt, A ;
Jagla, W ;
Popp, A ;
Leclair, S ;
Herrmann, K ;
Seiderer, J ;
Ochsenkühn, T ;
Göke, B ;
Auernhammer, CJ ;
Dambacher, J .
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2006, 290 (04) :G827-G838
[8]   Genome-guided design of a defined mouse microbiota that confers colonization resistance against Salmonella enterica serovar Typhimurium [J].
Brugiroux, Sandrine ;
Beutler, Markus ;
Pfann, Carina ;
Garzetti, Debora ;
Ruscheweyh, Hans-Joachim ;
Ring, Diana ;
Diehl, Manuel ;
Herp, Simone ;
Loetscher, Yvonne ;
Hussain, Saib ;
Bunk, Boyke ;
Pukall, Ruediger ;
Huson, Daniel H. ;
Muench, Philipp C. ;
McHardy, Alice C. ;
McCoy, Kathy D. ;
Macpherson, Andrew J. ;
Loy, Alexander ;
Clavel, Thomas ;
Berry, David ;
Stecher, Baerbel .
NATURE MICROBIOLOGY, 2017, 2 (02)
[9]   MHC class II engagement by its ligand LAG-3 (CD223) leads to a distinct pattern of chemokine and chemokine receptor expression by human dendritic cells [J].
Buisson, S ;
Triebel, F .
VACCINE, 2003, 21 (9-10) :862-868
[10]   Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology [J].
Buonocore, Sofia ;
Ahern, Philip P. ;
Uhlig, Holm H. ;
Ivanov, Ivaylo I. ;
Littman, Dan R. ;
Maloy, Kevin J. ;
Powrie, Fiona .
NATURE, 2010, 464 (7293) :1371-1375