Adoptive Transfer ; Animals ; B-Lymphocytes/cytology* ; B-Lymphocytes/immunology* ; Blotting, Western ; Carrier Proteins/genetics ; Carrier Proteins/immunology* ; Carrier Proteins/metabolism ; Cell Differentiation/immunology* ; Cell Proliferation ; Cell Survival/immunology ; Electrophoretic Mobility Shift Assay ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Homeostasis/immunology* ; Immunohistochemistry ; Mice ; Mice, Inbred C57BL ; Rapamycin-Insensitive Companion of mTOR Protein ; Signal Transduction/immunology ; TOR Serine-Threonine Kinases/genetics ; TOR Serine-Threonine Kinases/immunology ; TOR Serine-Threonine Kinases/metabolism
Keywords
Adoptive Transfer ; Animals ; B-Lymphocytes/cytology* ; B-Lymphocytes/immunology* ; Blotting, Western ; Carrier Proteins/genetics ; Carrier Proteins/immunology* ; Carrier Proteins/metabolism ; Cell Differentiation/immunology* ; Cell Proliferation ; Cell Survival/immunology ; Electrophoretic Mobility Shift Assay ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Homeostasis/immunology* ; Immunohistochemistry ; Mice ; Mice, Inbred C57BL ; Rapamycin-Insensitive Companion of mTOR Protein ; Signal Transduction/immunology ; TOR Serine-Threonine Kinases/genetics ; TOR Serine-Threonine Kinases/immunology ; TOR Serine-Threonine Kinases/metabolism
Abstract
The mammalian target of rapamycin (mTOR), an essential serine/threonine kinase, functions in biochemically distinct multiprotein complexes, but little is known about roles of the complexes in B cells. The acutely rapamycin-sensitive mTOR complex 1 (mTORC1) is defined by a core subunit Raptor, whereas mTORC2 lacks Raptor and, instead, has Rictor and SIN1 as distinct essential components. We now show that homeostasis and function of B cells require Rictor. Conditional deletion of Rictor before lymphoid specification impaired generation of mature follicular, marginal zone, and B1a B lymphocytes. Induced inactivation in adult mice caused cell-autonomous defects in B lymphoid homeostasis and antibody responses in vivo, along with affecting plasma cells in bone marrow. Survival of B lymphocytes depended on Rictor, which was vital for normal induction of prosurvival genes, suppression of proapoptotic genes, nuclear factor κB induction after B-cell receptor stimulation, and B-cell activating factor-induced nuclear factor κB2/p52 generation. Collectively, the findings provide evidence that mTOR signaling affects survival and proliferation of mature B lymphocytes, and establish Rictor as an important signal relay in B-cell homeostasis, fate, and functions.