WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity.

INTRODUCTION The essential role of actin cytoskeletal regulatory proteins in expression of effective immune responses is exemplified by the impaired immunity manifested by patients deficient for the Wiskott-Aldrich syndrome actin modulatory protein (WASp). Among other WASp-related drivers of actin rearrangement, the WASp family verprolin homologous protein 2 (WAVE2) is predominantly expressed in hematopoietic cells and has been implicated in the cytoskeletal remodeling required for T cell adhesion and organization of the immunological synapse. However, the precise roles of WAVE2 in modulating T cell functions that govern immunity remain unknown. RATIONALE WAVE2 stability and subcellular localization depend on its constitutive association with the ABI1/2 (Abelson interactor 1/2), HEM1 (hematopoietic protein 1), HSPC300 (haematopoietic stem/progenitor cell protein 300), and CYFIP1 (cytoplasmic FMR1 interacting protein 1) proteins, which together constitute a pentameric WAVE regulatory complex (WRC) that supports WAVE2 activation by the Rac guanosine triphosphatase and other stimulatory signals that trigger WAVE2-driven actin-related protein-2/3 (Arp2/3)–dependent actin nucleation. Genetic data implicating several WAVE2-associated WRC proteins in autoimmune disease and the established link between cytoskeletal regulator dysfunction and immune deficiency raise the possibility that WAVE2 represents an important effector of T cell contributions to immune competence. Thus, we derived WAVE2 T cell conditional knockout (Wave2cKO) mice to enable investigation of WAVE2 influence on T cell homeostasis and function. RESULTS Characterization of Wave2cKO mice expressing WAVE2-deficient T cells revealed numbers of peripheral T cells to be reduced in young ( CONCLUSION Our findings identify a critical role for WAVE2 in restraining T cell activation and effector differentiation, with T cell–selective WAVE2 ablation leading to combined immunodeficiency and autoimmune disease. The enhanced mTOR activation observed in WAVE2-deficient T cells and the suppression of disease in Wave2cKO mice treated with an mTOR inhibitor establish WAVE2 restriction of mTOR activity as a critical mechanistic pathway supporting T cell quiescence so as to maintain immune homeostasis and prevent inflammation and autoimmunity.