An MHC II-dependent Activation Loop Between Adipose Tissue Macrophages and CD4+ T Cells Controls Obesity-induced Inflammation

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2014 Oct 15

PMID 25310975

Citations 99

Authors

Kae Won Cho

David L Morris

Jennifer L DelProposto

Lynn Geletka

Brian Zamarron

Gabriel Martinez-Santibanez

Kevin A Meyer

Kanakadurga Singer

Robert W ORourke

Carey N Lumeng

Affiliations

Soon will be listed here.

Abstract

An adaptive immune response triggered by obesity is characterized by the activation of adipose tissue CD4(+) T cells by unclear mechanisms. We have examined whether interactions between adipose tissue macrophages (ATMs) and CD4(+) T cells contribute to adipose tissue metainflammation. Intravital microscopy identifies dynamic antigen-dependent interactions between ATMs and T cells in visceral fat. Mice deficient in major histocompatibility complex class II (MHC II) showed protection from diet-induced obesity. Deletion of MHC II expression in macrophages led to an adipose tissue-specific decrease in the effector/memory CD4(+) T cells, attenuation of CD11c(+) ATM accumulation, and improvement in glucose intolerance by increasing adipose tissue insulin sensitivity. Ablation experiments demonstrated that the maintenance of proliferating conventional T cells is dependent on signals from CD11c(+) ATMs in obese mice. These studies demonstrate the importance of MHCII-restricted signals from ATMs that regulate adipose tissue T cell maturation and metainflammation.

Citing Articles

Diverse Functions of Macrophages in Obesity and Metabolic Dysfunction-Associated Steatotic Liver Disease: Bridging Inflammation and Metabolism.

Jang J, Sung J, Huh J Immune Netw. 2025; 25(1):e12.

PMID: 40078789 PMC: 11896663. DOI: 10.4110/in.2025.25.e12.

The role of adipogenic niche resident cells in colorectal cancer progression in relation to obesity.

Domagalski M, Olszanska J, Pietraszek-Gremplewicz K, Nowak D Obes Rev. 2025; 26(4):e13873.

PMID: 39763022 PMC: 11884973. DOI: 10.1111/obr.13873.

Dynamic Roles and Expanding Diversity of Adipose Tissue Macrophages in Obesity.

Soedono S, Julietta V, Nawaz H, Cho K J Obes Metab Syndr. 2024; 33(3):193-212.

PMID: 39324219 PMC: 11443328. DOI: 10.7570/jomes24030.

Tryptophan Metabolism in Obesity: The Indoleamine 2,3-Dioxygenase-1 Activity and Therapeutic Options.

Engin A, Engin A Adv Exp Med Biol. 2024; 1460:629-655.

PMID: 39287867 DOI: 10.1007/978-3-031-63657-8_21.

Subcutaneous adipose tissue: Implications in dermatological diseases and beyond.

Ziadlou R, Pandian G, Hafner J, Akdis C, Stingl G, Maverakis E Allergy. 2024; 79(12):3310-3325.

PMID: 39206504 PMC: 11657049. DOI: 10.1111/all.16295.

References

Khanna K, Blair D, Vella A, McSorley S, Datta S, Lefrancois L . T cell and APC dynamics in situ control the outcome of vaccination. J Immunol. 2010; 185(1):239-52. PMC: 2997353. DOI: 10.4049/jimmunol.0901047. View

Podojil J, Miller S . Molecular mechanisms of T-cell receptor and costimulatory molecule ligation/blockade in autoimmune disease therapy. Immunol Rev. 2009; 229(1):337-55. PMC: 2845642. DOI: 10.1111/j.1600-065X.2009.00773.x. View

Lumeng C, Bodzin J, Saltiel A . Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007; 117(1):175-84. PMC: 1716210. DOI: 10.1172/JCI29881. View

Gautier E, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S . Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol. 2012; 13(11):1118-28. PMC: 3558276. DOI: 10.1038/ni.2419. View

Rangel-Moreno J, Moyron-Quiroz J, Carragher D, Kusser K, Hartson L, Moquin A . Omental milky spots develop in the absence of lymphoid tissue-inducer cells and support B and T cell responses to peritoneal antigens. Immunity. 2009; 30(5):731-43. PMC: 2754314. DOI: 10.1016/j.immuni.2009.03.014. View

Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson S . PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature. 2012; 486(7404):549-53. PMC: 3387339. DOI: 10.1038/nature11132. View

Khan I, Dai Perrard X, Perrard J, Mansoori A, Smith C, Wu H . Attenuated adipose tissue and skeletal muscle inflammation in obese mice with combined CD4+ and CD8+ T cell deficiency. Atherosclerosis. 2014; 233(2):419-428. PMC: 4094239. DOI: 10.1016/j.atherosclerosis.2014.01.011. View

Bertola A, Ciucci T, Rousseau D, Bourlier V, Duffaut C, Bonnafous S . Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients. Diabetes. 2012; 61(9):2238-47. PMC: 3425417. DOI: 10.2337/db11-1274. View

Mathis D . Immunological goings-on in visceral adipose tissue. Cell Metab. 2013; 17(6):851-859. PMC: 4264591. DOI: 10.1016/j.cmet.2013.05.008. View

10.

ORourke R, White A, Metcalf M, Winters B, Diggs B, Zhu X . Systemic inflammation and insulin sensitivity in obese IFN-γ knockout mice. Metabolism. 2012; 61(8):1152-61. PMC: 3457921. DOI: 10.1016/j.metabol.2012.01.018. View

11.

Mattioli B, Straface E, Quaranta M, Giordani L, Viora M . Leptin promotes differentiation and survival of human dendritic cells and licenses them for Th1 priming. J Immunol. 2005; 174(11):6820-8. DOI: 10.4049/jimmunol.174.11.6820. View

12.

Fabbrini E, Cella M, McCartney S, Fuchs A, Abumrad N, Pietka T . Association between specific adipose tissue CD4+ T-cell populations and insulin resistance in obese individuals. Gastroenterology. 2013; 145(2):366-74.e1-3. PMC: 3756481. DOI: 10.1053/j.gastro.2013.04.010. View

13.

Rocha V, Folco E, Sukhova G, Shimizu K, Gotsman I, Vernon A . Interferon-gamma, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity. Circ Res. 2008; 103(5):467-76. PMC: 2740384. DOI: 10.1161/CIRCRESAHA.108.177105. View

14.

Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A . Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med. 2009; 15(8):930-9. PMC: 3115752. DOI: 10.1038/nm.2002. View

15.

Morris D, Cho K, DelProposto J, Oatmen K, Geletka L, Martinez-Santibanez G . Adipose tissue macrophages function as antigen-presenting cells and regulate adipose tissue CD4+ T cells in mice. Diabetes. 2013; 62(8):2762-72. PMC: 3717880. DOI: 10.2337/db12-1404. View

16.

Surh C, Sprent J . Homeostasis of naive and memory T cells. Immunity. 2008; 29(6):848-62. DOI: 10.1016/j.immuni.2008.11.002. View

17.

Priceman S, Kujawski M, Shen S, Cherryholmes G, Lee H, Zhang C . Regulation of adipose tissue T cell subsets by Stat3 is crucial for diet-induced obesity and insulin resistance. Proc Natl Acad Sci U S A. 2013; 110(32):13079-84. PMC: 3740863. DOI: 10.1073/pnas.1311557110. View

18.

Do J, Valujskikh A, Vignali D, Fairchild R, Min B . Unexpected role for MHC II-peptide complexes in shaping CD8 T-cell expansion and differentiation in vivo. Proc Natl Acad Sci U S A. 2012; 109(31):12698-703. PMC: 3411949. DOI: 10.1073/pnas.1207219109. View

19.

Koltsova E, Garcia Z, Chodaczek G, Landau M, McArdle S, Scott S . Dynamic T cell-APC interactions sustain chronic inflammation in atherosclerosis. J Clin Invest. 2012; 122(9):3114-26. PMC: 3428082. DOI: 10.1172/JCI61758. View

20.

Martinez-Santibanez G, Cho K, Lumeng C . Imaging white adipose tissue with confocal microscopy. Methods Enzymol. 2014; 537:17-30. PMC: 4233125. DOI: 10.1016/B978-0-12-411619-1.00002-1. View