Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3.
Hyper-immunoglobulin E syndrome (HIES) is a primary immune deficiency characterized by abnormal and devastating susceptibility to a narrow spectrum of infections, most commonly Staphylococcus aureus and Candida albicans. Recent investigations have identified mutations in STAT3 in the majority of HIES patients studied. Despite the identification of the genetic cause of HIES, the mechanisms underlying the pathological features of this disease remain to be elucidated. Here, we demonstrate a failure of CD4+ T cells harboring heterozygous STAT3 mutations to generate interleukin 17-secreting (i.e., T helper [Th]17) cells in vivo and in vitro due to a failure to express sufficient levels of the Th17-specific transcriptional regulator retinoid-related orphan receptor t. Because Th17 cells are enriched for cells with specificities against fungal antigens, our results may explain the pattern of infection susceptibility characteristic of patients with HIES. Furthermore, they underscore the importance of Th17 responses in normal host defense against the common pathogens S. aureus and C. albicans.
Ma
Cindy S
CS
Immunology and Inflammation Program, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
Chew
Gary Y J
GY
Simpson
Nicholas
N
Priyadarshi
Archana
A
Wong
Melanie
M
Grimbacher
Bodo
B
Fulcher
David A
DA
Tangye
Stuart G
SG
Cook
Matthew C
MC
D000946:Antigens, Fungal / Q000276:immunology; D002176:Candida albicans / Q000276:immunology; D002177:Candidiasis / Q000235:genetics / Q000276:immunology; D002648:Child; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000172:deficiency* / Q000276:immunology; D007589:Job Syndrome / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008297:Male; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000276:immunology*; D013203:Staphylococcal Infections / Q000235:genetics / Q000276:immunology; D013211:Staphylococcus aureus / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D000946:Antigens, Fungal; D020381:Interleukin-17; D018160:Receptors, Cytoplasmic and Nuclear; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human