Biomaterial Database

WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity. 2021

Ming Liu, and Jinyi Zhang, and Benjamin D Pinder, and Qingquan Liu, and Dingyan Wang, and Hao Yao, and Yubo Gao, and Aras Toker, and Jimin Gao, and Alan Peterson, and Jia Qu, and Katherine A Siminovitch

Mount Sinai Hospital, Toronto, Ontario, Canada.

Cytoskeletal regulatory protein dysfunction has been etiologically linked to inherited diseases associated with immunodeficiency and autoimmunity, but the mechanisms involved are incompletely understood. Here, we show that conditional Wave2 ablation in T cells causes severe autoimmunity associated with increased mammalian target of rapamycin (mTOR) activation and metabolic reprogramming that engender spontaneous activation and accelerated differentiation of peripheral T cells. These mice also manifest diminished antigen-specific T cell responses associated with increased inhibitory receptor expression, dysregulated mitochondrial function, and reduced cell survival upon activation. Mechanistically, WAVE2 directly bound mTOR and inhibited its activation by impeding mTOR interactions with RAPTOR (regulatory-associated protein of mTOR) and RICTOR (rapamycin-insensitive companion of mTOR). Both the T cell defects and immunodysregulatory disease were ameliorated by pharmacological mTOR inhibitors. Thus, WAVE2 restraint of mTOR activation is an absolute requirement for maintaining the T cell homeostasis supporting adaptive immune responses and preventing autoimmunity.

UI	MeSH Term	Description	Entries
D007153	Immunologic Deficiency Syndromes	Syndromes in which there is a deficiency or defect in the mechanisms of immunity, either cellular or humoral.	Antibody Deficiency Syndrome,Deficiency Syndrome, Immunologic,Deficiency Syndromes, Antibody,Deficiency Syndromes, Immunologic,Immunologic Deficiency Syndrome,Immunological Deficiency Syndromes,Antibody Deficiency Syndromes,Deficiency Syndrome, Antibody,Deficiency Syndrome, Immunological,Deficiency Syndromes, Immunological,Immunological Deficiency Syndrome,Syndrome, Antibody Deficiency,Syndrome, Immunologic Deficiency,Syndrome, Immunological Deficiency,Syndromes, Antibody Deficiency,Syndromes, Immunologic Deficiency,Syndromes, Immunological Deficiency
D008213	Lymphocyte Activation	Morphologic alteration of small B LYMPHOCYTES or T LYMPHOCYTES in culture into large blast-like cells able to synthesize DNA and RNA and to divide mitotically. It is induced by INTERLEUKINS; MITOGENS such as PHYTOHEMAGGLUTININS, and by specific ANTIGENS. It may also occur in vivo as in GRAFT REJECTION.	Blast Transformation,Blastogenesis,Lymphoblast Transformation,Lymphocyte Stimulation,Lymphocyte Transformation,Transformation, Blast,Transformation, Lymphoblast,Transformation, Lymphocyte,Activation, Lymphocyte,Stimulation, Lymphocyte
D008810	Mice, Inbred C57BL	One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases.	Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D011948	Receptors, Antigen, T-Cell	Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens (CD3 COMPLEX). Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta (RECEPTORS, ANTIGEN, T-CELL, ALPHA-BETA) or gamma-delta (RECEPTORS, ANTIGEN, T-CELL, GAMMA-DELTA) chains.	Antigen Receptors, T-Cell,T-Cell Receptors,Receptors, T-Cell Antigen,T-Cell Antigen Receptor,T-Cell Receptor,Antigen Receptor, T-Cell,Antigen Receptors, T Cell,Receptor, T-Cell,Receptor, T-Cell Antigen,Receptors, T Cell Antigen,Receptors, T-Cell,T Cell Antigen Receptor,T Cell Receptor,T Cell Receptors,T-Cell Antigen Receptors
D002454	Cell Differentiation	Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs.	Differentiation, Cell,Cell Differentiations,Differentiations, Cell
D006706	Homeostasis	The processes whereby the internal environment of an organism tends to remain balanced and stable.	Autoregulation
D000076223	Regulatory-Associated Protein of mTOR	An adaptor protein component of the MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1 that forms stoichiometric complexes with TOR KINASES, which it negatively regulates. It functions as a positive regulator of RIBOSOMAL PROTEIN S6 KINASES.	RAPTOR Protein,RPTOR Protein,Regulatory Associated Protein of mTOR,mTOR Regulatory-Associated Protein
D000076226	Rapamycin-Insensitive Companion of mTOR Protein	An adaptor protein subunit of MTORC2 COMPLEX. It functions as a structural component and is phosphorylated by RIBOSOMAL PROTEIN S6 KINASES, integrating signals for cell growth and proliferation, especially during embryonic development.	RICTOR Protein,Rapamycin Insensitive Companion of mTOR Protein
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D001327	Autoimmune Diseases	Disorders that are characterized by the production of antibodies that react with host tissues or immune effector cells that are autoreactive to endogenous peptides.	Autoimmune Disease,Disease, Autoimmune,Diseases, Autoimmune