WASP helps T_Reg cells sting their prey

Wiskott–Aldrich syndrome (WAS) is a primary immunodeficiency resulting from defective expression of the WAS protein (WASP). Up to 70% of patients with WAS also develop some form of autoimmune disease. Given the role of naturally occurring CD4⁺CD25⁺ regulatory T (T_Reg) cells in preventing autoimmunity, three new studies have examined the role of WASP in the development and function of T_Reg cells. The three groups agree that WASP has an important role in T_Reg cells, but they propose slightly different explanations for its effects.

Both Humblet-Baron et al. and Marangoni et al. showed that WASP is not required for the normal thymic development of T_Reg cells, whereas Maillard et al. found decreased numbers of T_Reg cells in the thymus of Wasp^−/− mice, as well as in the spleen and lymph nodes. Marangoni et al. next showed that Wasp^−/− T_Reg cells had a decreased capacity to suppress the proliferation of both wild-type and Wasp^−/− effector T cells in vitro. Maillard et al. obtained similar in vitro results and further showed that, in contrast to wild-type T_Reg cells, Wasp^−/− T_Reg cells could not prevent the induction of colitis by the adoptive transfer of wild-type effector T cells in vivo.

Therefore, Marangoni et al. and Maillard et al. both conclude that WASP deficiency abrogates the suppressive activity of T_Reg cells, and Maillard et al. also propose that the decreased production of T_Reg cells has a role. The defect in the suppressive activity observed for Wasp^−/− T_Reg cells was shown to result partly from a defect in the production of transforming growth factor-β (Marangoni et al.) or interleukin-10 (IL-10) (Maillard et al.).

However, Humblet-Baron et al. showed that wild-type and Wasp^−/− T_Reg cells mediated equivalent suppression of Wasp^−/− effector T cells in vitro, but that the number of Wasp^−/− T_Reg cells in peripheral lymphoid compartments was decreased. On the basis of three independent in vivo mouse models, they propose that WASP deficiency decreases the competitive fitness of T_Reg cells, rather than their function. For example, when chimeric bone marrow containing a mixture of wild-type and Wasp^−/− cells was transplanted into lethally irradiated Wasp^−/− mice, there was a preferential expansion of wild-type compared with Wasp^−/− T_Reg-cell populations. The failure of adoptively transferred Wasp^−/− T_Reg cells to engraft in wild-type hosts (Marangoni et al.) and their defective homing to peripheral lymphoid organs (Maillard et al.) also lend support to the idea that Wasp^−/− T_Reg cells have decreased fitness.

Finally, all three groups considered the potential contribution of changes in effector T cells to the decreased activity of T_Reg cells in Wasp^−/− mice. Wasp^−/− effector T cells were not as effectively suppressed as wild-type effector T cells by wild-type T_Reg cells (Marangoni et al.), and both Marangoni et al. and Maillard et al. showed that the addition of exogenous IL-2 could partially rescue the suppression defect of Wasp^−/− T_Reg cells. Humblet-Baron et al. agree that the decreased competitive fitness of Wasp^−/− T_Reg cells could be exacerbated by decreased production of IL-2 by effector T cells in Wasp^−/− mice, although this does not explain the decreased fitness of Wasp^−/− T_Reg cells in Wasp^+/− female mice.