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Lrig1-expression confers suppressive function to CD4⁺ cells and is essential for averting autoimmunity via the Smad2/3/Foxp3 axis.

ABSTRACT: Regulatory T cells (T_reg) are CD4⁺ T cells with immune-suppressive function, which is defined by Foxp3 expression. However, the molecular determinants defining the suppressive population of T cells have yet to be discovered. Here we report that the cell surface protein Lrig1 is enriched in suppressive T cells and controls their suppressive behaviors. Within CD4⁺ T cells, T_reg cells express the highest levels of Lrig1, and the expression level is further increasing with activation. The Lrig1⁺ subpopulation from T helper (Th) 17 cells showed higher suppressive activity than the Lrig1^- subpopulation. Lrig1-deficiency impairs the suppressive function of T_reg cells, while Lrig1-deficient naïve T cells normally differentiate into other T cell subsets. Adoptive transfer of CD4⁺Lrig1⁺ T cells alleviates autoimmune symptoms in colitis and lupus nephritis mouse models. A monoclonal anti-Lrig1 antibody significantly improves the symptoms of experimental autoimmune encephalomyelitis. In conclusion, Lrig1 is an important regulator of suppressive T cell function and an exploitable target for treating autoimmune conditions.

SUBMITTER: Moon JS

PROVIDER: S-EPMC10477202 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Lrig1-expression confers suppressive function to CD4+ cells and is essential for averting autoimmunity via the Smad2/3/Foxp3 axis.

Moon Jae-Seung JS Ho Chun-Chang CC Park Jong-Hyun JH Park Kyungsoo K Shin Bo-Young BY Lee Su-Hyeon SH Sequeira Ines I Mun Chin Hee CH Shin Jin-Su JS Kim Jung-Ho JH Kim Beom Seok BS Noh Jin-Wook JW Lee Eui-Seon ES Son Ji Young JY Kim Yuna Y Lee Yeji Y Cho Hee H So SunHyeon S Park Jiyoon J Choi Eunsu E Oh Jong-Won JW Lee Sang-Won SW Morio Tomohiro T Watt Fiona M FM Seong Rho Hyun RH Lee Sang-Kyou SK

Nature communications 20230904 1

Regulatory T cells (Treg) are CD4+ T cells with immune-suppressive function, which is defined by Foxp3 expression. However, the molecular determinants defining the suppressive population of T cells have yet to be discovered. Here we report that the cell surface protein Lrig1 is enriched in suppressive T cells and controls their suppressive behaviors. Within CD4+ T cells, Treg cells express the highest levels of Lrig1, and the expression level is furthe ...[more]

PMID: 37666819

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Project description:ObjectiveThe approximately 45-cM insulin-dependent diabetes 9 (Idd9) region on mouse chromosome 4 harbors several different type 1 diabetes-associated loci. Nonobese diabetic (NOD) mice congenic for the Idd9 region of C57BL/10 (B10) mice, carrying antidiabetogenic alleles in three different Idd9 subregions (Idd9.1, Idd9.2, and Idd9.3), are strongly resistant to type 1 diabetes. However, the mechanisms remain unclear. This study aimed to define mechanisms underlying the type 1 diabetes resistance afforded by B10 Idd9.1, Idd9.2, and/or Idd9.3.Research design and methodsWe used a reductionist approach that involves comparing the fate of a type 1 diabetes-relevant autoreactive CD8(+) T-cell population, specific for residues 206-214 of islet-specific glucose 6 phosphatase catalytic subunit-related protein (IGRP(206-214)), in noncongenic versus B10 Idd9-congenic (Idd9.1 + Idd9.2 + Idd9.3, Idd9.2 + Idd9.3, Idd9.1, Idd9.2, and Idd9.3) T-cell receptor (TCR)-transgenic (8.3) NOD mice.ResultsMost of the protective effect of Idd9 against 8.3-CD8(+) T-cell-enhanced type 1 diabetes was mediated by Idd9.1. Although Idd9.2 and Idd9.3 afforded some protection, the effects were small and did not enhance the greater protective effect of Idd9.1. B10 Idd9.1 afforded type 1 diabetes resistance without impairing the developmental biology or intrinsic diabetogenic potential of autoreactive CD8(+) T-cells. Studies in T- and B-cell-deficient 8.3-NOD.B10 Idd9.1 mice revealed that this antidiabetogenic effect was mediated by endogenous, nontransgenic T-cells in a B-cell-independent manner. Consistent with this, B10 Idd9.1 increased the suppressive function and antidiabetogenic activity of the FoxP3(+)CD4(+)CD25(+) T-cell subset in both TCR-transgenic and nontransgenic mice.ConclusionsA gene(s) within Idd9.1 regulates the development and function of FoxP3(+)CD4(+)CD25(+) regulatory T-cells and, in turn, the activation of CD8(+) effector T-cells in the pancreatic draining lymph nodes, without affecting their development or intrinsic diabetogenic potential.

Dataset Information

Lrig1-expression confers suppressive function to CD4⁺ cells and is essential for averting autoimmunity via the Smad2/3/Foxp3 axis.

Publications

Lrig1-expression confers suppressive function to CD4<sup>+</sup> cells and is essential for averting autoimmunity via the Smad2/3/Foxp3 axis.

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