When T cells cannot help.

Wiskott-Aldrich syndrome is caused by mutations in the WASP gene, which affects the function of most hematopoietic cells and leads to immunodeficiency.1 In this issue of Blood, Morales-Tirado and colleagues show that T helper cells lacking WASp have a selective deficiency in their memory response.2 The Wiskott-Aldrich syndrome protein (WASp) is a crucial regulator of actin polymerization. Its gene is located on the X chromosome and when mutated, it leads to thrombocytopenia, immunodeficiency, and eczema. WASp is expressed in hematopoietic cells and in its absence, migration, adhesion, activation, and antigen uptake malfunction. It has previously been shown that WASp plays a role in T-cell activation, being important for the regulation of the so-called immunologic synapse.3 This membrane structure, crucial for activation of T cells, is formed between T cells and antigen-presenting cells and is composed of clusters of T-cell receptor, adhesion molecules, and signaling molecules. It has also been suggested that WASp can regulate transcriptional activation in T cells independent of its role in actin polymerization.4 CD4 T helper cells can be divided into subpopulations, depending on expression of transcription factors and/or cytokines (see figure). Th1 cells secrete IL-2 and IFN , which are particularly important for cellmediated responses, whereas Th2 cells secrete IL-4, IL-5, and IL-13, which play important roles in humoral immunity and atopic allergy. There are also more newly discovered CD4 cell populations such as Th17 cells, T follicular T helper cells, and Treg cells.5,6 In this issue of Blood, Morales-Tirado et al show that cytokine secretion from activated primed T helper cells is affected in the absence of WASp.2 They demonstrate that absence of WASp leads to lower IFN and IL-4 secretion in primed, in vitro–activated Th1 and Th2 cells, respectively. Secretion of IFN can be rescued by signals from antigenpresenting cells, whereas secretion of IL-4 cannot. Levels of other Th2 cytokines, such as IL-5, IL-10, and IL-13, were also lower in the absence of WASp. Early events in Th2 differentiation are not affected by the absence of WASp and there is no measurable defect in transcriptional activation of the il4 gene in the memory response. Thus, there is an uncoupling of IL-4 protein production and transcription in Th2 effector function. MoralesTirado et al give evidence that this effect could be due to a deficiency in activation of the signaling molecule ERK, which might regulate translation or protein stability. In their experiment, Morales-Tirado et al went on to analyze T helper cell function in parasite responses in vivo, studying WASpdeficient T cells in a WASp-sufficient environment. They found that T cells mediated protective immunity and parasite clearance in a Th1 response, but were unable to support a Th2 response to the nematode Nippostrongylus brasiliensis. Thus, there was a significant delay in parasite clearance, which seemed to be due to lower IL-4 and IL-13 levels as well as reduced recruitment of innate effectors to infected tissue. Differentiation of CD4 T cells. In the thymus, a subpopulation of CD4 cells become positive for the transcription factor Foxp3 and develop into regulatory T (Treg) cells.6 CD4 Foxp3 cells leave the thymus and give rise to Th0 cells. Depending on the type of antigen-dependent signals, Th0 cells develop into Th1, Th2, follicular T helper (Tfh), or Th17 cells.5