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PMID: 10544204 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Antigen receptor-induced activation and cytoskeletal rearrangement are impaired in Wiskott-Aldrich syndrome protein-deficient lymphocytes.

The Journal of experimental medicine ·Vol. 190 ·No. 9 ·1999-11-01 ·Pages 1329-42

Zhang J, Shehabeldin A, da Cruz LA, Butler J, Somani AK, McGavin M, Kozieradzki I, dos Santos AO, Nagy A, Grinstein S, Penninger JM, Siminovitch KA

Abstract

The Wiskott-Aldrich syndrome protein (WASp) has been implicated in modulation of lymphocyte activation and cytoskeletal reorganization. To address the mechanisms whereby WASp subserves such functions, we have examined WASp roles in lymphocyte development and activation using mice carrying a WAS null allele (WAS(-)(/)(-)). Enumeration of hemopoietic cells in these animals revealed total numbers of thymocytes, peripheral B and T lymphocytes, and platelets to be significantly diminished relative to wild-type mice. In the thymus, this abnormality was associated with impaired progression from the CD44(-)CD25(+) to the CD44(-)CD25(-) stage of differentiation. WASp-deficient thymocytes and T cells also exhibited impaired proliferation and interleukin (IL)-2 production in response to T cell antigen receptor (TCR) stimulation, but proliferated normally in response to phorbol ester/ionomycin. This defect in TCR signaling was associated with a reduction in TCR-evoked upregulation of the early activation marker CD69 and in TCR-triggered apoptosis. While induction of TCR-zeta, ZAP70, and total protein tyrosine phosphorylation as well as mitogen-activated protein kinase (MAPK) and stress-activated protein/c-Jun NH(2)-terminal kinase (SAPK/JNK) activation appeared normal in TCR-stimulated WAS(-)(/)(-) cells, TCR-evoked increases in intracellular calcium concentration were decreased in WASp-deficient relative to wild-type cells. WAS(-)(/)(-) lymphocytes also manifested a marked reduction in actin polymerization and both antigen receptor capping and endocytosis after TCR stimulation, whereas WAS(-)(/)(-) neutrophils exhibited reduced phagocytic activity. Together, these results provide evidence of roles for WASp in driving lymphocyte development, as well as in the translation of antigen receptor stimulation to proliferative or apoptotic responses, cytokine production, and cytoskeletal rearrangement. The data also reveal a role for WASp in modulating endocytosis and phagocytosis and, accordingly, suggest that the immune deficit conferred by WASp deficiency reflects the disruption of a broad range of cellular behaviors.

MeSH Terms
Actins/metabolism Animals B-Lymphocytes/immunology CD3 Complex/immunology Cell Count Cell Differentiation Cytoskeleton/metabolism Gene Targeting Immunologic Capping Interleukin-2/metabolism Lymph Nodes/immunology Lymphocyte Activation/immunology Mice Mice, Knockout Neutrophils/immunology Phagocytosis/immunology Proteins/genetics,immunology Receptors, Antigen, T-Cell/metabolism Signal Transduction/immunology Spleen/immunology T-Lymphocytes/immunology Wiskott-Aldrich Syndrome/genetics,immunology Wiskott-Aldrich Syndrome Protein
Chemicals
Actins CD3 Complex Interleukin-2 Proteins Receptors, Antigen, T-Cell Was protein, mouse Wiskott-Aldrich Syndrome Protein
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Zhang J
Department of Medicine, University of Toronto, Ontario, Canada M5G 1X5.
Shehabeldin A
da Cruz L A
Butler J
Somani A K
McGavin M
Kozieradzki I
dos Santos A O
Nagy A
Grinstein S
Penninger J M
Siminovitch K A
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.190.9.1329
Published
1999-11-01
Pages
1329-42
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2195687
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.190.9.1329 PMC Full Text View journal details
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