Dysregulated immunity in PID\xa0patients with low GARP expression on Tregs due to mutations in LRRC32

Peter Lehmkuhl,Magdalena Gentz,Hendrik Schulze-Koops,Andres Caballero Garcia De Otezya,Alla Skapenko,Bodo Grimbacher

doi: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.

Highlights

Primary immunodeficiency (PID) is a heterogeneous group of disorders characterized by impaired immune development and function due to single-gene mutations
Several mutations leading to immune dysregulation, such as FOXP3 mutations causing immune dysregulation, polyendocrinopathy, enteropathy, or X-linked syndrome[3] and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) mutations resulting in CTLA4 haploinsufficiency,[4,5] have been identified
We report two PID patients with previously undescribed leucine-rich repeat containing 32 (LRRC32) mutations suffering from severe immune dysregulation and exhibiting Treg defects

Summary

Introduction

Primary immunodeficiency (PID) is a heterogeneous group of disorders characterized by impaired immune development and function due to single-gene mutations. The clinical manifestations of PID are variable and include severe infections, autoimmunity and malignancies.[1] PID conditions that are associated with autoimmune diseases due to defects in the regulation of selftolerance are referred to as immune dysregulation diseases.[2]. Due to the heterogeneity of these diseases, it is highly likely that mutations in other genes may cause immune dysregulation. The identification of these mutations has critical clinical implications

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