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

Jinyi Zhang, Amro Shehabeldin, Luis A G Da Cruz, Jeffrey Butler, Ally-Khan Somani, Mary McGavin, Ivona Kozieradzki, Antonio O. Dos Santos, Andras Nagy, Sergio Grinstein, Josef M. Penninger, Katherine A. Siminovitch

Research output: Contribution to journalArticle

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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-ζ, ZAP70, and total protein tyrosine phosphorylation as well as mitogen- activated protein kinase (MAPK) and stress-activated protein/c-Jun NH2- 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.

Original languageEnglish (US)
Pages (from-to)1329-1341
Number of pages13
JournalJournal of Experimental Medicine
Volume190
Issue number9
DOIs
StatePublished - Nov 1 1999
Externally publishedYes

Fingerprint

Wiskott-Aldrich Syndrome Protein
Antigen Receptors
T-Cell Antigen Receptor
Lymphocytes
Thymocytes
Lymphocyte Activation
Endocytosis
Receptor Aggregation
T-Lymphocytes
Protein Deficiency
Ionomycin
JNK Mitogen-Activated Protein Kinases
Phorbol Esters
Heat-Shock Proteins
Mitogen-Activated Protein Kinases
Phagocytosis
Polymerization
Thymus Gland
Interleukin-2
Tyrosine

Keywords

  • Antigen receptor signaling
  • Cytoskeletal rearrangement
  • Immunodeficiency
  • Lymphocyte activation
  • Wiskott-Aldrich syndrome protein

ASJC Scopus subject areas

  • Immunology

Cite this

Antigen receptor-induced activation and cytoskeletal rearrangement are impaired in Wiskott-Aldrich syndrome protein-deficient lymphocytes. / Zhang, Jinyi; Shehabeldin, Amro; Da Cruz, Luis A G; Butler, Jeffrey; Somani, Ally-Khan; McGavin, Mary; Kozieradzki, Ivona; Dos Santos, Antonio O.; Nagy, Andras; Grinstein, Sergio; Penninger, Josef M.; Siminovitch, Katherine A.

In: Journal of Experimental Medicine, Vol. 190, No. 9, 01.11.1999, p. 1329-1341.

Research output: Contribution to journalArticle

Zhang, J, Shehabeldin, A, Da Cruz, LAG, Butler, J, Somani, A-K, McGavin, M, Kozieradzki, I, Dos Santos, AO, Nagy, A, Grinstein, S, Penninger, JM & Siminovitch, KA 1999, 'Antigen receptor-induced activation and cytoskeletal rearrangement are impaired in Wiskott-Aldrich syndrome protein-deficient lymphocytes', Journal of Experimental Medicine, vol. 190, no. 9, pp. 1329-1341. https://doi.org/10.1084/jem.190.9.1329
Zhang, Jinyi ; Shehabeldin, Amro ; Da Cruz, Luis A G ; Butler, Jeffrey ; Somani, Ally-Khan ; McGavin, Mary ; Kozieradzki, Ivona ; Dos Santos, Antonio O. ; Nagy, Andras ; Grinstein, Sergio ; Penninger, Josef M. ; Siminovitch, Katherine A. / Antigen receptor-induced activation and cytoskeletal rearrangement are impaired in Wiskott-Aldrich syndrome protein-deficient lymphocytes. In: Journal of Experimental Medicine. 1999 ; Vol. 190, No. 9. pp. 1329-1341.
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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-ζ, ZAP70, and total protein tyrosine phosphorylation as well as mitogen- activated protein kinase (MAPK) and stress-activated protein/c-Jun NH2- 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.",
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