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

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Abstract
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 CD4−CD8−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 CD4−CD8+single-positive (SP) cells and increased percentage of CD69lowCD24lowand CD62LlowSP 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.