Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis

Marita Bosticardo; Yasuhiro Yamazaki; Jennifer Cowan; Giuliana Giardino; Cristina Corsino; Giulia Scalia; Rosaria Prencipe; Melanie Ruffner; David A Hill; Inga Sakovich; Irma Yemialyanava; Jonathan S Tam; Nurcicek Padem; Melissa E Elder; John W Sleasman; Elena Perez; Hana Niebur; Christine M Seroogy; Svetlana Sharapova; Jennifer Gebbia; Gary Ira Kleiner; Jane Peake; Jordan K Abbott; Erwin W Gelfand; Elena Crestani; Catherine Biggs; Manish J Butte; Nicholas Hartog; Anthony Hayward; Karin Chen; Jennifer Heimall; Filiz Seeborg; Lisa M Bartnikas; Megan A Cooper; Claudio Pignata; Avinash Bhandoola; Luigi D Notarangelo

doi:10.1016/j.ajhg.2019.07.014

Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis

Am J Hum Genet. 2019 Sep 5;105(3):549-561. doi: 10.1016/j.ajhg.2019.07.014. Epub 2019 Aug 22.

Authors

Marita Bosticardo¹, Yasuhiro Yamazaki¹, Jennifer Cowan², Giuliana Giardino³, Cristina Corsino¹, Giulia Scalia⁴, Rosaria Prencipe³, Melanie Ruffner⁵, David A Hill⁵, Inga Sakovich⁶, Irma Yemialyanava⁶, Jonathan S Tam⁷, Nurcicek Padem⁸, Melissa E Elder⁹, John W Sleasman¹⁰, Elena Perez¹¹, Hana Niebur¹², Christine M Seroogy¹³, Svetlana Sharapova⁶, Jennifer Gebbia¹⁴, Gary Ira Kleiner¹⁴, Jane Peake¹⁵, Jordan K Abbott¹⁶, Erwin W Gelfand¹⁶, Elena Crestani¹⁷, Catherine Biggs¹⁸, Manish J Butte¹⁹, Nicholas Hartog²⁰, Anthony Hayward²¹, Karin Chen²², Jennifer Heimall⁵, Filiz Seeborg²³, Lisa M Bartnikas¹⁷, Megan A Cooper²⁴, Claudio Pignata³, Avinash Bhandoola², Luigi D Notarangelo²⁵

Affiliations

¹ Laboratory of Clinical Immunology and Microbiology, IDGS, DIR, NIAID, NIH, Bethesda, MD 20892, USA.
² Laboratory of Genome Integrity, CCR, NCI, NIH, Bethesda, MD 20892, USA.
³ Department of Translational Medical Sciences Federico II University, Naples 80138, Italy.
⁴ Laboratory of Clinical research and Advanced Diagnostics, CEINGE Biotecnologie Avanzate, Naples 80131, Italy.
⁵ Division of Allergy and Immunology, Department of Pediatrics, Children's Hospital Philadelphia, Philadelphia, PA 19104, USA.
⁶ Immunology Lab, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk 223053, Belarus.
⁷ Division of Clinical Immunology and Allergy, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
⁸ Division of Allergy and Immunology, Lurie Children's Hospital, Chicago, IL 60611, USA.
⁹ Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA.
¹⁰ Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27705, USA.
¹¹ Allergy Associates of the Palm Beaches, North Palm Beach, FL 33408, USA.
¹² Division of Pediatric Allergy and Immunology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
¹³ Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.
¹⁴ Department of Pediatric Allergy and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
¹⁵ Division of Paediatric Immunology and Allergy, Lady Cilento Children's Hospital, University of Queensland School of Medicine, South Brisbane, QLD 4101, Australia.
¹⁶ Immunodeficiency Diagnosis and Treatment Program, Department of Pediatrics, National Jewish Health, Denver, CO 80206, USA.
¹⁷ Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA.
¹⁸ Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC V6H 0B3, Canada.
¹⁹ Division of Allergy, Immunology and Rheumatology, University of California at Los Angeles, Los Angeles, CA 90095, USA.
²⁰ Spectrum Health Allergy and Immunology, Grand Rapids, MI 49525, USA.
²¹ Division of Allergy and Immunology, Department of Pediatrics, Brown University and Rhode Island Hospital, Providence, RI 02905, USA.
²² Division of Allergy and Immunology, Department of Pediatrics, University of Utah, Salt Lake City, UT 84112, USA.
²³ Section of Allergy, Immunology and Rheumatology & Center for Human Immunobiology, Department of Pediatrics, Texas Children's Hospital, Houston, TX 77030, USA.
²⁴ Department of Pediatrics, Division of Rheumatology, Washington University in St. Louis, MO 63110, USA.
²⁵ Laboratory of Clinical Immunology and Microbiology, IDGS, DIR, NIAID, NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].

Abstract

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4⁺ but lower than normal CD8⁺ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1^nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.

Keywords: FOXN1; SCID; T cell receptor excision circles; T lymphocytes; newborn screening; thymopoiesis; thymus.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Animals
Child, Preschool
Female
Forkhead Transcription Factors / genetics*
Forkhead Transcription Factors / physiology
Heterozygote*
Humans
Infant
Infant, Newborn
Lymphopenia / genetics*
Male
Mice
Mice, SCID
Middle Aged
T-Lymphocytes / metabolism*
Thymus Gland / cytology*
Young Adult

Substances

Forkhead Transcription Factors
Whn protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding