Combined immunodeficiency due to ICOSLG deficiency

Primary Immunodeficiencies (PIDs) are inborn errors of immunity that represent naturally occurring experimental models to decipher human immunobiology. In this study, we report on a patient with combined immunodeficiency, who suffered from recurrent respiratory tract and DNA-based viral infections associated with hypogammaglobulinemia and panlymphopenia. In addition, he had moderate neutropenia but without associated prototypical pyogenic infections. Using whole exome and Sanger gene sequencing, we identified a homozygous mutation in the Inducible T-Cell Costimulator Ligand gene (ICOSLG; c.657C>G; p.N219K). Whereas wild-type ICOSL is expressed at the cell surface, the ICOSLN219K mutation abrogates cell surface expression, with retention of protein in the endoplasmic reticulum (ER)/Golgi apparatus, predicted to be due to a conformational change and significant alterations in biochemical properties. ICOSLN219K diminished T cell costimulatory activity and impaired transendothelial lymphocyte migration, contributing to the observed compromise in adaptive immunity. Moreover, endothelial expression of mutant ICOSL decreased neutrophil transmigration, by reducing the proper localization of E-Selectin and ICAM-1 at the cell surface. Our study identifies human ICOSLG deficiency as a novel cause of a combined immunodeficiency.