CRIg, a tissue-resident macrophage specific immune checkpoint molecule, promotes immunological tolerance in NOD mice, via a dual role in effector and regulatory T cells.
How tissue-resident macrophages (TRM) impact adaptive immune responses remains poorly understood. We report novel mechanisms by which TRMs regulate T cell activities at tissue sites. These mechanisms are mediated by the complement receptor of immunoglobulin family (CRIg). Using animal models for autoimmune type 1 diabetes (T1D), we found that CRIg+ TRMs formed a protective barrier surrounding pancreatic islets. Genetic ablation of CRIg exacerbated islet inflammation and local T cell activation. CRIg exhibited a dual function of attenuating early T cell activation and promoting the differentiation of Foxp3+ regulatory (Treg) cells. More importantly, CRIg stabilized the expression of Foxp3 in Treg cells, by enhancing their responsiveness to interleukin-2. The expression of CRIg in TRMs was postnatally regulated by gut microbial signals and metabolites. Thus, environmental cues instruct TRMs to express CRIg, which functions as an immune checkpoint molecule to regulate adaptive immunity and promote immune tolerance.
Pubmed ID: 29171836 RIS Download
Research resources used in this publication
- BISMA (RRID:SCR_000688) (web application)
- ImageJ (RRID:SCR_003070) (software resource)
- FlowJo (RRID:SCR_008520) (software resource)
-
B6.SJL-Ptprca Pepc
- NOD.129X1(Cg)-Foxp3tm2Tch/DvsJ (RRID:IMSR_JAX:025097) (organism)
- NOD/ShiLtJ (RRID:IMSR_JAX:001976) (organism)
- C57BL/6J (RRID:IMSR_JAX:000664) (organism)
Additional research tools detected in this publication
Antibodies used in this publication
- FITC anti-mouse CD4 (RRID:AB_312713)
- PE anti-mouse CD4 (RRID:AB_312715)
- PE/Cyanine7 anti-mouse CD8a (RRID:AB_312761)
- PE/Cyanine7 anti-mouse CD25 (RRID:AB_312865)
- Pacific Blue(TM) anti-mouse/human CD11b (RRID:AB_755986)
- NOT AN ANTIBODY PerCP/Cy5.5 Streptavidin (RRID:AB_2716577)
- Alexa Fluor® 647 Anti-Smad2 (pS465/pS467)/Smad3 (pS423/pS425) (RRID:AB_2716578)
- Stat5 (pY694) (RRID:AB_10894188)
- Phospho-S6 (Ser235, Ser236) Monoclonal Antibody (cupk43k), PE, eBioscience (RRID:AB_2572666)
- Phospho-AKT1 (Ser473) Monoclonal Antibody (SDRNR), APC, eBioscience (RRID:AB_2573309)
- PerCP/Cyanine5.5 anti-ERK1/2 Phospho (Thr202/Tyr204) (RRID:AB_2629710)
- Phospho-ZAP70/Syk (Tyr319, Tyr352) Monoclonal Antibody (n3kobu5), PE, eBioscience (RRID:AB_2572664)
- FOXP3 Monoclonal Antibody (FJK-16s), eFluor™ 450, eBioscience (RRID:AB_1518812)
- PE anti-mouse IFN-gamma (RRID:AB_315402)
- APC anti-mouse IL-17A (RRID:AB_536018)
- PE anti-mouse CD335 (NKp46) (RRID:AB_2235755)
- PE anti-mouse CD19 (RRID:AB_313643)
- PE anti-mouse CD11c (RRID:AB_313777)
- PE anti-mouse/human CD11b (RRID:AB_312791)
- APC anti-mouse F4/80 (RRID:AB_893481)
- PerCP/Cyanine5.5 anti-mouse CD69 (RRID:AB_2260065)
- PE anti-mouse CD25 (RRID:AB_312857)
- Biotin anti-mouse CD122 (IL-2Rbeta) (RRID:AB_313226)
- CD278 (ICOS) Monoclonal Antibody (7E.17G9), PE-Cyanine7, eBioscience™ (RRID:AB_2573563)
- PE anti-mouse/human Helios (RRID:AB_10660749)
- Alexa Fluor(R) 647 anti-mouse CD90.2 (Thy1.2) (RRID:AB_492888)
- PerCP/Cyanine5.5 anti-rat CD90/mouse CD90.1 (Thy-1.1) (RRID:AB_961437)
- PE anti-mouse CD8a (RRID:AB_312747)
- APC anti-mouse CD4 (RRID:AB_312719)
- Alexa Fluor(R) 488 anti-mouse TCR beta chain (RRID:AB_493344)
- APC anti-mouse CD45.2 (RRID:AB_389211)
- PerCP/Cyanine5.5 anti-mouse CD45.1 (RRID:AB_893346)
- APC/Cyanine7 anti-mouse CD45 (RRID:AB_312981)
- Purified Rat Anti-Mouse CD16/CD32 (Mouse BD Fc Block™) Clone 2.4G2 (RRID:AB_394656)
- Mouse Anti-TGF-beta 1,-2,-3 Monoclonal antibody, Unconjugated, Clone 1d11 (RRID:AB_357931)
- Ultra-LEAF(TM) Purified anti-mouse CD28 (RRID:AB_11150408)
- Ultra-LEAF(TM) Purified anti-mouse CD3epsilon (RRID:AB_11149115)
Associated grants
- Agency: NIDDK NIH HHS, United States
Id: P30 DK063491 - Agency: NCATS NIH HHS, United States
Id: UL1 TR000100
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This is a list of tools and resources that we have found mentioned in this publication.
GE Healthcare (tool)
RRID:SCR_000004
A commercial antibody supplier and provider of various services.
View all literature mentionsBioLegend (tool)
RRID:SCR_001134
Commercial antibody supplier and developer for biomedical research. These products are compatible with use in flow cytometry and mass cytometry, immunoprecipitation and chip, western blotting, immunofluorescence microscopy, and quantitative multiplexing.
View all literature mentionsJackson Laboratory (tool)
RRID:SCR_004633
An independent, nonprofit organization focused on mammalian genetics research to advance human health. Their mission is to discover the genetic basis for preventing, treating, and curing human disease, and to enable research for the global biomedical community. Jackson Laboratory breeds and manages colonies of mice as resources for other research institutions and laboratories, along with providing software and techniques. Jackson Lab also conducts genetic research and provides educational material for various educational levels.
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View all literature mentionsThermo Fisher Scientific (tool)
RRID:SCR_008452
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View all literature mentionsQIAGEN (tool)
RRID:SCR_008539
A commercial organization which provides assay technologies to isolate DNA, RNA, and proteins from any biological sample. Assay technologies are then used to make specific target biomolecules, such as the DNA of a specific virus, visible for subsequent analysis.
View all literature mentionsAnaSpec (tool)
RRID:SCR_002114
Commercial supplier of antibodies, reagents, and dyes for research.
View all literature mentionsGenentech (tool)
RRID:SCR_003997
A biotechnology corporation that uses human genetic information to discover, develop, manufacture and commercialize medicines to treat patients with serious or life-threatening medical conditions.
View all literature mentionsFITC anti-mouse CD4 (antibody)
RRID:AB_312713
This monoclonal targets CD4
View all literature mentionsPE anti-mouse CD4 (antibody)
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RRID:AB_312761
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RRID:AB_312865
This monoclonal targets CD25
View all literature mentionsPacific Blue(TM) anti-mouse/human CD11b (antibody)
RRID:AB_755986
This monoclonal targets CD11b
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RRID:AB_2716577
This unknown targets Biotin
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RRID:AB_2716578
This monoclonal targets Phosphorylated Human Smad2 Peptide
View all literature mentionsStat5 (pY694) (antibody)
RRID:AB_10894188
This monoclonal targets Stat5 (pY694)
View all literature mentionsPhospho-S6 (Ser235, Ser236) Monoclonal Antibody (cupk43k), PE, eBioscience (antibody)
RRID:AB_2572666
This monoclonal targets Phospho-S6 (Ser235, Ser236)
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RRID:AB_2573309
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RRID:AB_2629710
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RRID:AB_2235755
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RRID:AB_313643
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This monoclonal targets F4/80
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RRID:AB_312857
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RRID:AB_313226
This monoclonal targets CD122
View all literature mentionsCD278 (ICOS) Monoclonal Antibody (7E.17G9), PE-Cyanine7, eBioscience™ (antibody)
RRID:AB_2573563
This monoclonal targets CD278 (ICOS)
View all literature mentionsPE anti-mouse/human Helios (antibody)
RRID:AB_10660749
This monoclonal targets Helios
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RRID:AB_492888
This monoclonal targets CD90.2
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RRID:AB_961437
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RRID:AB_389211
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RRID:AB_312981
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RRID:AB_357931
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RRID:AB_11150408
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RRID:AB_11149115
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View all literature mentionsBISMA (web application)
RRID:SCR_000688
An online tool for the analysis of bisulfite sequencing DNA methylation data. The software has specificity and quality control functions that allow the user to compile a set of sequences.
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RRID:SCR_003070
Open source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.
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RRID:SCR_008520
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B6.SJL-Ptprca Pepc/BoyJ (organism)
RRID:IMSR_JAX:002014
Mus musculus with name B6.SJL-Ptprca Pepc
NOD.129X1(Cg)-Foxp3tm2Tch/DvsJ (organism)
RRID:IMSR_JAX:025097
Mus musculus with name NOD.129X1(Cg)-Foxp3tm2Tch/DvsJ from IMSR.
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RRID:IMSR_JAX:001976
Mus musculus with name NOD/ShiLtJ from IMSR.
View all literature mentionsC57BL/6J (organism)
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