Dysregulated immunity in PID patients with low GARP expression on Tregs due to mutations in LRRC32
Open Access
- 31 May 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cellular & Molecular Immunology
- Vol. 18 (7), 1677-1691
- https://doi.org/10.1038/s41423-021-00701-z
Abstract
Immune dysregulation diseases are characterized by heterogeneous clinical manifestations and may have severe disease courses. The identification of the genetic causes of these diseases therefore has critical clinical implications. We performed whole-exome sequencing of patients with immune dysregulation disorders and identified two patients with previously undescribed mutations in LRRC32, which encodes glycoprotein A repetitions predominant (GARP). These patients were characterized by markedly reduced numbers and frequencies of regulatory T cells (Tregs). Tregs with mutated LRRC32 exhibited strongly diminished cell-surface GARP expression and reduced suppressor function. In a model of conditional Garp deficiency in mice, we confirmed increased susceptibility to inflammatory diseases once GARP expression on Tregs was decreased. Garp deficiency led to an unstable Treg phenotype due to diminished Foxp3 protein acetylation and stability. Our study reinforces the understanding of the immunological mechanisms of immune dysregulation and expands the knowledge on the immunological function of GARP as an important regulator of Treg stability.Keywords
This publication has 43 references indexed in Scilit:
- GARP regulates the bioavailability and activation of TGFβMolecular Biology of the Cell, 2012
- Expression of GARP selectively identifies activated human FOXP3+ regulatory T cellsProceedings of the National Academy of Sciences of the United States of America, 2009
- GARP (LRRC32) is essential for the surface expression of latent TGF-β on platelets and activated FOXP3 + regulatory T cellsProceedings of the National Academy of Sciences of the United States of America, 2009
- Functional Delineation and Differentiation Dynamics of Human CD4+ T Cells Expressing the FoxP3 Transcription FactorImmunity, 2009
- Heterogeneity of natural Foxp3 + T cells: A committed regulatory T-cell lineage and an uncommitted minor population retaining plasticityProceedings of the National Academy of Sciences of the United States of America, 2009
- FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repressionProceedings of the National Academy of Sciences of the United States of America, 2007
- Decreased FOXP3 levels in multiple sclerosis patientsJournal of Neuroscience Research, 2005
- Control of Regulatory T Cell Development by the Transcription Factor Foxp3Science, 2003
- CD4+CD25+ Regulatory T Cells Can Mediate Suppressor Function in the Absence of Transforming Growth Factor β1 Production and ResponsivenessThe Journal of Experimental Medicine, 2002
- Origin of regulatory T cells with known specificity for antigenNature Immunology, 2002