Early defects in human T-cell development severely affect distribution and maturation of thymic stromal cells: possible implications for the pathophysiology of Omenn syndrome.
Thymocytes and thymic epithelial cell (TEC) cross-talk is crucial to preserve thymic architecture and function, including maturation of TECs and dendritic cells, and induction of mechanisms of central tolerance. We have analyzed thymic maturation and organization in 9 infants with various genetic defects leading to complete or partial block in T-cell development. Profound abnormalities of TEC differentiation (with lack of AIRE expression) and severe reduction of thymic dendritic cells were identified in patients with T-negative severe combined immunodeficiency, reticular dysgenesis, and Omenn syndrome. The latter also showed virtual absence of thymic Foxp3(+) T cells. In contrast, an IL2RG-R222C hypomorphic mutation permissive for T-cell development allowed for TEC maturation, AIRE expression, and Foxp3(+) T cells. Our data provide evidence that severe defects of thymopoiesis impinge on TEC homeostasis and may affect deletional and nondeletional mechanisms of central tolerance, thus favoring immune dysreactive manifestations, as in Omenn syndrome.
Poliani
Pietro Luigi
PL
Department of Pathology, University of Brescia, Brescia, Italy.
Facchetti
Fabio
F
Ravanini
Maria
M
Gennery
Andrew Richard
AR
Villa
Anna
A
Roifman
Chaim M
CM
Notarangelo
Luigi D
LD
D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007223:Infant; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D008231:Lymphopenia / Q000276:immunology / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D017154:Stromal Cells / Q000276:immunology* / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology* / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics; D000096927:AIRE Protein
D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D053631:Interleukin Receptor Common gamma Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D000096927:AIRE Protein; C418974:FOXP3 protein, human; C507941:IL2RG protein, human; C499311:RAG2 protein, human