Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes.
X-linked neutropenia (XLN) is caused by activating mutations in the Wiskott-Aldrich syndrome protein (WASP) that result in aberrant autoinhibition. Although patients with XLN appear to have only defects in myeloid lineages, we hypothesized that activating mutations of WASP are likely to affect the immune system more broadly. We generated mouse models to assess the role of activating WASP mutations associated with XLN (XLN-WASP) in lymphocytes. XLN-WASP is expressed stably in B and T cells and induces a marked increase in polymerized actin. XLN-WASP-expressing B and T cells migrate toward chemokines but fail to adhere normally. In marked contrast to WASP-deficient cells, XLN-WASP-expressing T cells proliferate normally in response to cell-surface receptor activation. However, XLN-WASP-expressing B cells fail to proliferate and secrete lower amounts of antibodies. Moreover, XLN-WASP expression in lymphocytes results in modestly increased apoptosis associated with increased genomic instability. These data indicate that there are unique requirements for the presence and activation status of WASP in B and T cells and that WASP-activating mutations interfere with lymphocyte cell survival and genomic stability.
Westerberg
Lisa S
LS
Gastrointestinal Unit, Center for the Study of Inflammatory Bowel Diseases, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02114, USA.
Meelu
Parool
P
Baptista
Marisa
M
Eston
Michelle A
MA
Adamovich
David A
DA
Cotta-de-Almeida
Vinicius
V
Seed
Brian
B
Rosen
Michael K
MK
Vandenberghe
Peter
P
Thrasher
Adrian J
AJ
Klein
Christoph
C
Alt
Frederick W
FW
Snapper
Scott B
SB
D000199:Actins / Q000378:metabolism*; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology*; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009503:Neutropenia / Q000235:genetics* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics*
D000199:Actins; D050505:Mutant Proteins; D011956:Receptors, Cell Surface; D051316:Wiskott-Aldrich Syndrome Protein