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

Overview

Journal Elife

Specialty Biology

Date 2017 Nov 25

PMID 29171836

Citations 31

Authors

Xiaomei Yuan

Bi-Huei Yang

Yi Dong

Asami Yamamura

Wenxian Fu

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Macrophages in graft-versus-host disease (GVHD): dual roles as therapeutic tools and targets.

Raoufi A, Soleimani Samarkhazan H, Nouri S, Khaksari M, Abbasi Sourki P, Sargazi Aval O Clin Exp Med. 2025; 25(1):73.

PMID: 40048037 PMC: 11885342. DOI: 10.1007/s10238-025-01588-0.

VSIG4 tumor-associated macrophages mediate neutrophil infiltration and impair antigen-specific immunity in aggressive cancers through epigenetic regulation of SPP1.

Pan Z, Chen J, Xu T, Cai A, Han B, Li Y J Exp Clin Cancer Res. 2025; 44(1):45.

PMID: 39920772 PMC: 11803937. DOI: 10.1186/s13046-025-03303-z.

Exploring perinatal mesenchymal stromal cells as a potential therapeutic strategy for rheumatoid arthritis.

Alivernini S, Masserdotti A, Magatti M, Cargnoni A, Papait A, Silini A Heliyon. 2025; 11(1):e41438.

PMID: 39811302 PMC: 11732555. DOI: 10.1016/j.heliyon.2024.e41438.

Tissue-Resident Macrophages in Cancer: Friend or Foe?.

Chi J, Gao Q, Liu D Cancer Med. 2024; 13(21):e70387.

PMID: 39494816 PMC: 11533131. DOI: 10.1002/cam4.70387.

Exploring the immune microenvironment of osteosarcoma through T cell exhaustion-associated gene expression: a study on prognosis prediction.

Zhu J, Yuan J, Arya S, Du Z, Liu X, Jia J Front Immunol. 2024; 14:1265098.

PMID: 38169731 PMC: 10758463. DOI: 10.3389/fimmu.2023.1265098.

References

Emamaullee J, Davis J, Merani S, Toso C, Elliott J, Thiesen A . Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice. Diabetes. 2009; 58(6):1302-11. PMC: 2682686. DOI: 10.2337/db08-1113. View

Bailey-Bucktrout S, Bluestone J . Regulatory T cells: stability revisited. Trends Immunol. 2011; 32(7):301-6. PMC: 3129467. DOI: 10.1016/j.it.2011.04.002. View

Yue X, Trifari S, Aijo T, Tsagaratou A, Pastor W, Zepeda-Martinez J . Control of Foxp3 stability through modulation of TET activity. J Exp Med. 2016; 213(3):377-97. PMC: 4813667. DOI: 10.1084/jem.20151438. View

Depis F, Kwon H, Mathis D, Benoist C . Unstable FoxP3+ T regulatory cells in NZW mice. Proc Natl Acad Sci U S A. 2016; 113(5):1345-50. PMC: 4747713. DOI: 10.1073/pnas.1524660113. View

Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y . T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity. 2012; 37(5):785-99. DOI: 10.1016/j.immuni.2012.09.010. View

Chen W, Jin W, Hardegen N, Lei K, Li L, Marinos N . Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003; 198(12):1875-86. PMC: 2194145. DOI: 10.1084/jem.20030152. View

Wang L, Pino-Lagos K, de Vries V, Guleria I, Sayegh M, Noelle R . Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc Natl Acad Sci U S A. 2008; 105(27):9331-6. PMC: 2442817. DOI: 10.1073/pnas.0710441105. View

Thornton A, Korty P, Tran D, Wohlfert E, Murray P, Belkaid Y . Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol. 2010; 184(7):3433-41. PMC: 3725574. DOI: 10.4049/jimmunol.0904028. View

Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig M, von Boehmer H . Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol. 2005; 6(12):1219-27. DOI: 10.1038/ni1265. View

10.

Sefik E, Geva-Zatorsky N, Oh S, Konnikova L, Zemmour D, Manson McGuire A . MUCOSAL IMMUNOLOGY. Individual intestinal symbionts induce a distinct population of RORγ⁺ regulatory T cells. Science. 2015; 349(6251):993-7. PMC: 4700932. DOI: 10.1126/science.aaa9420. View

11.

Burchill M, Yang J, Vogtenhuber C, Blazar B, Farrar M . IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J Immunol. 2006; 178(1):280-90. DOI: 10.4049/jimmunol.178.1.280. View

12.

Iwasaki A, Medzhitov R . Control of adaptive immunity by the innate immune system. Nat Immunol. 2015; 16(4):343-53. PMC: 4507498. DOI: 10.1038/ni.3123. View

13.

Bending D, De La Pena H, Veldhoen M, Phillips J, Uyttenhove C, Stockinger B . Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J Clin Invest. 2009; 119(3):565-72. PMC: 2648686. DOI: 10.1172/JCI37865. View

14.

Kalekar L, Schmiel S, Nandiwada S, Lam W, Barsness L, Zhang N . CD4(+) T cell anergy prevents autoimmunity and generates regulatory T cell precursors. Nat Immunol. 2016; 17(3):304-14. PMC: 4755884. DOI: 10.1038/ni.3331. View

15.

Feng Y, Arvey A, Chinen T, van der Veeken J, Gasteiger G, Rudensky A . Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell. 2014; 158(4):749-763. PMC: 4151558. DOI: 10.1016/j.cell.2014.07.031. View

16.

Grivennikov S, Greten F, Karin M . Immunity, inflammation, and cancer. Cell. 2010; 140(6):883-99. PMC: 2866629. DOI: 10.1016/j.cell.2010.01.025. View

17.

Zheng Y, Josefowicz S, Chaudhry A, Peng X, Forbush K, Rudensky A . Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature. 2010; 463(7282):808-12. PMC: 2884187. DOI: 10.1038/nature08750. View

18.

Livanos A, Greiner T, Vangay P, Pathmasiri W, Stewart D, McRitchie S . Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice. Nat Microbiol. 2016; 1(11):16140. PMC: 5808443. DOI: 10.1038/nmicrobiol.2016.140. View

19.

Gorgani N, He J, Katschke Jr K, Helmy K, Xi H, Steffek M . Complement receptor of the Ig superfamily enhances complement-mediated phagocytosis in a subpopulation of tissue resident macrophages. J Immunol. 2008; 181(11):7902-8. DOI: 10.4049/jimmunol.181.11.7902. View

20.

Medzhitov R . Origin and physiological roles of inflammation. Nature. 2008; 454(7203):428-35. DOI: 10.1038/nature07201. View