Loss of human ICOSL results in combined immunodeficiency

Abstract

Primary immunodeficiencies represent naturally occurring experimental models to decipher human immunobiology. We report a patient with combined immunodeficiency, marked by recurrent respiratory tract and DNA-based viral infections, hypogammaglobulinemia, and panlymphopenia. He also developed moderate neutropenia but without prototypical pyogenic infections. Using whole-exome sequencing, we identified a homozygous mutation in the inducible T cell costimulator ligand gene (ICOSLG; c.657C>G; p.N219K). Whereas WT ICOSL is expressed at the cell surface, the ICOSLN219K mutation abrogates surface localization: mutant protein is retained in the endoplasmic reticulum/Golgi apparatus, which is predicted to result from deleterious conformational and biochemical changes. ICOSLN219K diminished B cell costimulation of T cells, providing a compelling basis for the observed defect in antibody and memory B cell generation. Interestingly, ICOSLN219K also impaired migration of lymphocytes and neutrophils across endothelial cells, which normally express ICOSL. These defects likely contributed to the altered adaptive immunity and neutropenia observed in the patient, respectively. Our study identifies human ICOSLG deficiency as a novel cause of a combined immunodeficiency.

Inducible T‐cell co‐stimulator: Signaling mechanisms in T follicular helper cells and beyond

“…The ICOS ligand (ICOSL, CD275, B7h, B7RP‐1, B7‐H2, GL50) belongs to the B7 family of co‐stimulatory ligands characterized with two extracellular immunoglobulin domains, one TM domain, and a cytoplasmic tail. Consistent with data that both ICOS and ICOSL mutations in mice and humans display congruent humoral immune defects, binding assays support that ICOS specifically binds to a unique ligand ICOSL . In contrast to ligands for CD28 (CD80 and CD86), whose expression is restricted to antigen‐presenting cells, ICOSL is also expressed on ILCs, and non‐hematopoietic cells .…”

“…It has been shown that several hours of ICOS ligation without TCR engagement induces actin remodeling and T‐cell polarization . This actin remodeling capacity of ICOS‐ICOSL interaction may facilitate transendothelial migration of activated T cells through an endothelial layer . We found that within a few minutes of ICOS ligation, small GTPases (Cdc42 and RhoA) were activated.…”

“…Indeed, transgenic mice that constitutively overexpress ICOS in all T cells behave like ICOSL‐deficient mice in antibody responses, while mice with constitutively elevated ICOSL in all B cells by mutations of ADAM10 and/or 17 show dysregulated T‐cell responses . Furthermore, patients with genetic mutations in ICOSLG (gene encoding ICOSL) or MAP3K14 (gene encoding NF‐kB inducing kinase) that disrupted proper expression of ICOSL on the B cell surface suffer from recurrent respiratory infections with hypogammaglobulinemia and altered Tfh responses. Unlike T cells that express only ICOS but not ICOSL, ILCs express both ICOS and ICOSL on the cell surface in a constitutive manner .…”

“…Second, the availability of co‐stimulatory ligands may explain some of the distinct functions of ICOS. In addition to antigen‐presenting cells, ICOSL has been found to be inducibly expressed on fibroblasts, endothelial cells, epithelial cells, muscle fibers, and podocytes under inflammatory conditions. Thus, ICOS co‐stimulation can dominate under situations where CD28 ligands are limited such as in inflamed tissues .…”

Next generation sequencing analysis of consecutive Russian patients with clinical suspicion of inborn errors of immunity

“…The list of genes implicated in the pathogenesis of immunerelated disease is constantly growing, so some of the very recently identified gene candidates (eg, RIPK1, ICOSLG, CYBC1) could not be considered in our NGS panel. [30][31][32][33] Furthermore, our NGS test could not reliably identify copy number variations (CNVs), as the adaptation of NGS to CNV testing requires additional bioinformatics and analytical efforts. 34 It is relevant to mention that CNVs appear to be uncommon for PID patients.…”