Wiskott–Aldrich syndrome protein (WASP) and N-WASP are critical for T cell development

V Cotta-de-Almeida, L Westerberg… - Proceedings of the …, 2007 - National Acad Sciences
V Cotta-de-Almeida, L Westerberg, MH Maillard, D Onaldi, H Wachtel, P Meelu, U Chung…
Proceedings of the National Academy of Sciences, 2007National Acad Sciences
Although T cell dysfunction and lymphopenia are key features of immunodeficient patients
with the Wiskott–Aldrich syndrome and Wiskott–Aldrich syndrome protein (WASP)-deficient
mice, T cell development appears relatively normal. We hypothesized that N-WASP, a
ubiquitously expressed homologue of WASP, may serve a redundant function with WASP.
To examine the unique and redundant activities of WASP and N-WASP, we generated ES
cells devoid of WASP and N-WASP [double knockout (DKO)] and used the RAG-2-deficient …
Although T cell dysfunction and lymphopenia are key features of immunodeficient patients with the Wiskott–Aldrich syndrome and Wiskott–Aldrich syndrome protein (WASP)-deficient mice, T cell development appears relatively normal. We hypothesized that N-WASP, a ubiquitously expressed homologue of WASP, may serve a redundant function with WASP. To examine the unique and redundant activities of WASP and N-WASP, we generated ES cells devoid of WASP and N-WASP [double knockout (DKO)] and used the RAG-2-deficient blastocyst complementation system to generate DKO lymphocytes. Moreover, we mated WASP KO mice with mice containing a conditionally targeted N-WASP allele and used the Cre-loxP system to generate mice lacking WASP and N-WASP in T cells [conditional DKO (cDKO)]. In both systems, N-WASP-deficient cells were indistinguishable from WT cells. In contrast, T cell development in DKO and cDKO mice was markedly altered, as shown by thymic hypocellularity and reduced numbers of peripheral T cells. We found that the combined activity of WASP and N-WASP was important for CD4CD8 double-negative (DN)-to-CD4+CD8+ double-positive (DP) cell transition, and this may be partly explained by reduced cycling DN3 cells. In addition, decreased migratory responses of CD4+CD8 and CD4CD8+ single-positive (SP) cells and increased percentage of CD69lowCD24low and CD62Llow SP cells in cDKO cells imply retention of SP cells in the thymus. In summary, this study suggests that, although WASP serves a unique role for peripheral T cell function, T cell development depends on the combined activity of WASP and N-WASP.
National Acad Sciences