Abstract
The Wiskott-Aldrich syndrome (WAS) protein (WASp) is a regulator of actin cytoskeleton in hematopoietic cells. Mutations of the WASp gene cause WAS. Although WASp is involved in various immune cell functions, its role in invariant natural killer T (iNKT) cells has never been investigated. Defects of iNKT cells could indeed contribute to several WAS features, such as recurrent infections and high tumor incidence. We found a profound reduction of circulating iNKT cells in WAS patients, directly correlating with the severity of clinical phenotype. To better characterize iNKT cell defect in the absence of WASp, we analyzed was-/- mice. iNKT cell numbers were signifcantly reduced in the thymus and periphery of was-/- mice as compared with wild-type controls. Moreover analysis of was-/- iNKT cell maturation revealed a complete arrest at the CD44+ NK1.1- intermediate stage. Notably, generation of BM chimeras demonstrated a was -/- iNKT cell-autonomous developmental defect. was-/- iNKT cells were also functionally impaired, as suggested by the reduced secretion of interleukin 4 and interferon γ upon in vivo activation. Altogether, these results demonstrate the relevance of WASp in integrating signals critical for development and functional differentiation of iNKT cells and suggest that defects in these cells may play a role in WAS pathology.
| Original language | English |
|---|---|
| Pages (from-to) | 735-742 |
| Number of pages | 8 |
| Journal | Journal of Experimental Medicine |
| Volume | 206 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 13 2009 |
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ASJC Scopus subject areas
- Immunology
- Immunology and Allergy
- Medicine(all)
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The Wiskott-Aldrich syndrome protein is required for iNKT cell maturation and function. / Locci, Michela; Ghici, Elena Dra; Marangoni, Francesco; Bosticardo, Marita; Catucci, Marco; Aiuti, Alessandro; Cancrini, Caterina; Marodi, Laszlo; Espanol, Teresa; Bredius, Robbert G M; Thrasher, Adrian J.; Schulz, Ansgar; Litzman, Jiri; Roncarolo, Maria Grazia; Casorati, Giulia; Dellabona, Paolo; Villa, Anna.
In: Journal of Experimental Medicine, Vol. 206, No. 4, 13.04.2009, p. 735-742.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The Wiskott-Aldrich syndrome protein is required for iNKT cell maturation and function
AU - Locci, Michela
AU - Ghici, Elena Dra
AU - Marangoni, Francesco
AU - Bosticardo, Marita
AU - Catucci, Marco
AU - Aiuti, Alessandro
AU - Cancrini, Caterina
AU - Marodi, Laszlo
AU - Espanol, Teresa
AU - Bredius, Robbert G M
AU - Thrasher, Adrian J.
AU - Schulz, Ansgar
AU - Litzman, Jiri
AU - Roncarolo, Maria Grazia
AU - Casorati, Giulia
AU - Dellabona, Paolo
AU - Villa, Anna
PY - 2009/4/13
Y1 - 2009/4/13
N2 - The Wiskott-Aldrich syndrome (WAS) protein (WASp) is a regulator of actin cytoskeleton in hematopoietic cells. Mutations of the WASp gene cause WAS. Although WASp is involved in various immune cell functions, its role in invariant natural killer T (iNKT) cells has never been investigated. Defects of iNKT cells could indeed contribute to several WAS features, such as recurrent infections and high tumor incidence. We found a profound reduction of circulating iNKT cells in WAS patients, directly correlating with the severity of clinical phenotype. To better characterize iNKT cell defect in the absence of WASp, we analyzed was-/- mice. iNKT cell numbers were signifcantly reduced in the thymus and periphery of was-/- mice as compared with wild-type controls. Moreover analysis of was-/- iNKT cell maturation revealed a complete arrest at the CD44+ NK1.1- intermediate stage. Notably, generation of BM chimeras demonstrated a was -/- iNKT cell-autonomous developmental defect. was-/- iNKT cells were also functionally impaired, as suggested by the reduced secretion of interleukin 4 and interferon γ upon in vivo activation. Altogether, these results demonstrate the relevance of WASp in integrating signals critical for development and functional differentiation of iNKT cells and suggest that defects in these cells may play a role in WAS pathology.
AB - The Wiskott-Aldrich syndrome (WAS) protein (WASp) is a regulator of actin cytoskeleton in hematopoietic cells. Mutations of the WASp gene cause WAS. Although WASp is involved in various immune cell functions, its role in invariant natural killer T (iNKT) cells has never been investigated. Defects of iNKT cells could indeed contribute to several WAS features, such as recurrent infections and high tumor incidence. We found a profound reduction of circulating iNKT cells in WAS patients, directly correlating with the severity of clinical phenotype. To better characterize iNKT cell defect in the absence of WASp, we analyzed was-/- mice. iNKT cell numbers were signifcantly reduced in the thymus and periphery of was-/- mice as compared with wild-type controls. Moreover analysis of was-/- iNKT cell maturation revealed a complete arrest at the CD44+ NK1.1- intermediate stage. Notably, generation of BM chimeras demonstrated a was -/- iNKT cell-autonomous developmental defect. was-/- iNKT cells were also functionally impaired, as suggested by the reduced secretion of interleukin 4 and interferon γ upon in vivo activation. Altogether, these results demonstrate the relevance of WASp in integrating signals critical for development and functional differentiation of iNKT cells and suggest that defects in these cells may play a role in WAS pathology.
UR - http://www.scopus.com/inward/record.url?scp=65549150035&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=65549150035&partnerID=8YFLogxK
U2 - 10.1084/jem.20081773
DO - 10.1084/jem.20081773
M3 - Article
C2 - 19307326
AN - SCOPUS:65549150035
VL - 206
SP - 735
EP - 742
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 4
ER -